Cereblon ligands and bifunctional compounds comprising the same

ABSTRACT

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 15/953,108, filed on Apr. 13, 2018, which is a Continuation-in-Partof U.S. patent application Ser. No. 14/792,414, filed on Jul. 6, 2015,which claims the benefit of U.S. Provisional Patent Application62/171,090, filed on Jun. 4, 2015, and is a Continuation-in-Part of U.S.patent application Ser. No. 14/686,640, filed on Apr. 14, 2015, whichclaims priority to U.S. Provisional Application Ser. No. 61/979,351,filed on Apr. 4, 2014; all of which are incorporated herein by referencein their entirety.

INCORPORATION BY REFERENCE

U.S. patent application Ser. No. 15/230,354, filed on Aug. 5, 2016,published as U.S. Patent Application Publication No. 2017/0065719; andU.S. patent application Ser. No. 15/801,243, filed on 1 Nov. 2017; andU.S. patent application Ser. No. 15/206,497 filed 11 Jul. 2016; and U.S.patent application Ser. No. 15/209,648 filed 13 Jul. 2016; and U.S.patent application Ser. No. 15/730,728, filed on Oct. 11, 2017; U.S.patent application Ser. No. 15/829,541, filed on Dec. 1, 2017; U.S.patent application Ser. No. 15/881,318, filed on Jan. 26, 2018; and U.S.patent application Ser. No. 14/686,640, filed on Apr. 14, 2015,published as U.S. Patent Application Publication No. 2015/0291562; andU.S. patent application Ser. No. 14/792,414, filed on Jul. 6, 2015,published as U.S. Patent Application Publication No. 2016/0058872; andU.S. patent application Ser. No. 14/371,956, filed on Jul. 11, 2014,published as U.S. Patent Application Publication No. 2014/0356322; andU.S. patent application Ser. No. 15/074,820, filed on Mar. 18, 2016,published as U.S. Patent Application Publication No. 2016/0272639; andU.S. patent application Ser. No. 15/885,671, filed on 31 Jan. 2018, areincorporated herein by reference in their entirety. Furthermore, allreferences cited herein are incorporated by reference herein in theirentirety.

FIELD OF THE INVENTION

The description provides imide-based compounds, including bifunctionalcompounds comprising the same, and associated methods of use. Thebifunctional compounds are useful as modulators of targetedubiquitination, especially with respect to a variety of polypeptides andother proteins, which are degraded and/or otherwise inhibited bybifunctional compounds according to the present disclosure.

BACKGROUND

Most small molecule drugs bind enzymes or receptors in tight andwell-defined pockets. On the other hand, protein-protein interactionsare notoriously difficult to target using small molecules due to theirlarge contact surfaces and the shallow grooves or flat interfacesinvolved. E3 ubiquitin ligases (of which hundreds are known in humans)confer substrate specificity for ubiquitination, and therefore, are moreattractive therapeutic targets than general proteasome inhibitors due totheir specificity for certain protein substrates. The development ofligands of E3 ligases has proven challenging, in part due to the factthat they must disrupt protein-protein interactions. However, recentdevelopments have provided specific ligands which bind to these ligases.For example, since the discovery of nutlins, the first small molecule E3ligase inhibitors, additional compounds have been reported that targetE3 ligases but the field remains underdeveloped.

One E3 ligase with therapeutic potential is the von Hippel-Lindau (VHL)tumor suppressor. VHL comprises the substrate recognition subunit/E3ligase complex VCB, which includes elongins B and C, and a complexincluding Cullin-2 and Rbx1. The primary substrate of VHL is HypoxiaInducible Factor 1α (HIF-1α), a transcription factor that upregulatesgenes such as the pro-angiogenic growth factor VEGF and the red bloodcell inducing cytokine erythropoietin in response to low oxygen levels.We generated the first small molecule ligands of Von Hippel Lindau (VHL)to the substrate recognition subunit of the E3 ligase, VCB, an importanttarget in cancer, chronic anemia and ischemia, and obtained crystalstructures confirming that the compound mimics the binding mode of thetranscription factor HIF-1α, the major substrate of VHL.

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance. Cereblon forms an E3 ubiquitin ligasecomplex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A),and regulator of cullins 1 (ROC1). This complex ubiquitinates a numberof other proteins. Through a mechanism which has not been completelyelucidated, cereblon ubquitination of target proteins results inincreased levels of fibroblast growth factor 8 (FGF8) and fibroblastgrowth factor 10 (FGF10). FGF8 in turn regulates a number ofdevelopmental processes, such as limb and auditory vesicle formation.The net result is that this ubiquitin ligase complex is important forlimb outgrowth in embryos. In the absence of cereblon, DDB1 forms acomplex with DDB2 that functions as a DNA damage-binding protein.

Thalidomide, which has been approved for the treatment of a number ofimmunological indications, has also been approved for the treatment ofcertain neoplastic diseases, including multiple myeloma. In addition tomultiple myeloma, thalidomide and several of its analogs are alsocurrently under investigation for use in treating a variety of othertypes of cancer. While the precise mechanism of thalidomide's anti-tumoractivity is still emerging, it is known to inhibit angiogenesis. Recentliterature discussing the biology of the imides includes Lu et alScience 343, 305 (2014) and Kronke et al Science 343, 301 (2014).

Significantly, thalidomide and its analogs e.g. pomolinamiode andlenalinomide, are known to bind cereblon. These agents bind to cereblon,altering the specificity of the complex to induce the ubiquitination anddegradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factorsessential for multiple myeloma growth. Indeed, higher expression ofcereblon has been linked to an increase in efficacy of imide drugs inthe treatment of multiple myeloma.

An ongoing need exists in the art for effective treatments for disease,especially hyperplasias and cancers, such as multiple myeloma. However,non-specific effects, and the inability to target and modulate certainclasses of proteins altogether, such as transcription factors, remain asobstacles to the development of effective anti-cancer agents. As such,small molecule therapeutic agents that leverage or potentiate cereblon'ssubstrate specificity and, at the same time, are “tunable” such that awide range of protein classes can be targeted and modulated withspecificity would be very useful as a therapeutic.

BRIEF SUMMARY OF THE INVENTION

The present disclosure describes bifunctional compounds which functionto recruit endogenous proteins to an E3 Ubiquitin Ligase fordegradation, and methods of using the same. In particular, the presentdisclosure provides bifunctional or proteolysis targeting chimeric(PROTAC) compounds, which find utility as modulators of targetedubiquitination of a variety of polypeptides and other proteins, whichare then degraded and/or otherwise inhibited by the bifunctionalcompounds as described herein. An advantage of the compounds providedherein is that a broad range of pharmacological activities is possible,consistent with the degradation/inhibition of targeted polypeptides fromvirtually any protein class or family. In addition, the descriptionprovides methods of using an effective amount of the compounds asdescribed herein for the treatment or amelioration of a diseasecondition, such as cancer, e.g., multiple myeloma.

As such, in one aspect the disclosure provides novel imide-basedcompounds as described herein.

In an additional aspect, the disclosure provides bifunctional or PROTACcompounds, which comprise an E3 Ubiquitin Ligase binding moiety (i.e., aligand for an E3 Ubiquitin Ligase or “ULM” group), and a moiety thatbinds a target protein (i.e., a protein/polypeptide targeting ligand or“PTM” group) such that the target protein/polypeptide is placed inproximity to the ubiquitin ligase to effect degradation (and inhibition)of that protein. In a preferred embodiment, the ULM is a cereblon E3Ubiquitin Ligase binding moiety (i.e., a “CLM”). For example, thestructure of the bifunctional compound can be depicted as:

The respective positions of the PTM and CLM moieties as well as theirnumber as illustrated herein is provided by way of example only and isnot intended to limit the compounds in any way. As would be understoodby the skilled artisan, the bifunctional compounds as described hereincan be synthesized such that the number and position of the respectivefunctional moieties can be varied as desired.

In certain embodiments, the bifunctional compound further comprises achemical linker (“L”). In this example, the structure of thebifunctional compound can be depicted as:

where PTM is a protein/polypeptide targeting moiety, L is a linker, andCLM is a cereblon E3 ubiquitin ligase binding moiety.

In certain preferred embodiments, the E3 Ubiquitin Ligase is cereblon.As such, in certain additional embodiments, the CLM of the bifunctionalcompound comprises chemistries such as imide, amide, thioamide,thioimide derived moieties. In additional embodiments, the CLM comprisesa phthalimido group or an analog or derivative thereof. In stilladditional embodiments, the CLM comprises a phthalimido-glutarimidegroup or an analog or derivative thereof. In still other embodiments,the CLM comprises a member of the group consisting of thalidomide,lenalidomide, pomalidomide, and analogs or derivatives thereof.

In certain embodiments, the compounds as described herein comprisemultiple CLMs, multiple PTMs, multiple chemical linkers or a combinationthereof.

In any aspect or embodiment described herein, the ULM (ubiquitinationligase modulator) can be Von Hippel-Lindau E3 ubiquitin ligase (VHL)binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety(CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligasebinding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety(i.e., a “ILM”). In any aspect or embodiments described herein, thebifunctional compound includes at least one additional E3 ligase bindingmoiety selected from the group consisting of VLM, VLM′, CLM, CLM′, MLM,MLM′, ILM, ILM′, or a combination thereof. For example, there can be atleast 1, 2, 3, 4, or 5 additional E3 ligase binding moieties.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., cancer. In yet another aspect, thepresent disclosure provides a method of ubiquitinating/degrading atarget protein in a cell. In certain embodiments, the method comprisesadministering a bifunctional compound as described herein comprising anCLM and a PTM, preferably linked through a linker moiety, as otherwisedescribed herein, wherein the CLM is coupled to the PTM and wherein theCLM recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase,preferably an E3 ubiquitin ligase such as, e.g., cereblon) and the PTMrecognizes the target protein such that degradation of the targetprotein will occur when the target protein is placed in proximity to theubiquitin ligase, thus resulting in degradation/inhibition of theeffects of the target protein and the control of protein levels. Thecontrol of protein levels afforded by the present disclosure providestreatment of a disease state or condition, which is modulated throughthe target protein by lowering the level of that protein in the cells ofa patient.

In an additional aspect, the description provides a method for assessing(i.e., determining and/or measuring) a CLM's binding affinity. Incertain embodiments, the method comprises providing a test agent orcompound of interest, for example, an agent or compound having an imidemoiety, e.g., a phthalimido group, phthalimido-glutarimide group,derivatized thalidomide, derivatized lenalidomide or derivatizedpomalidomide, and comparing the cereblon binding affinity and/orinhibitory activity of the test agent or compound as compared to anagent or compound known to bind and/or inhibit the activity of cereblon.

In still another aspect, the description provides methods for treatingor emeliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,wherein the composition is effective for treating or ameliorating thedisease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The preceding general areas of utility are given by way of example onlyand are not intended to be limiting on the scope of the presentdisclosure and appended claims. Additional objects and advantagesassociated with the compositions, methods, and processes of the presentdisclosure will be appreciated by one of ordinary skill in the art inlight of the instant claims, description, and examples. For example, thevarious aspects and embodiments of the invention may be utilized innumerous combinations, all of which are expressly contemplated by thepresent description. These additional advantages objects and embodimentsare expressly included within the scope of the present disclosure. Thepublications and other materials used herein to illuminate thebackground of the invention, and in particular cases, to provideadditional details respecting the practice, are incorporated byreference.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate several embodiments of the presentdisclosure and, together with the description, serve to explain theprinciples of the invention. The drawings are only for the purpose ofillustrating an embodiment of the invention and are not to be construedas limiting the invention. Further objects, features and advantages ofthe invention will become apparent from the following detaileddescription taken in conjunction with the accompanying figures showingillustrative embodiments of the invention, in which:

FIGS. 1A and 1B. Illustration of general principle for PROTAC function.(A) Exemplary PROTACs comprise a protein targeting moiety (PTM; darklyshaded rectangle), a ubiquitin ligase binding moiety (ULM; lightlyshaded triangle), and optionally a linker moiety (L; black line)coupling or tethering the PTM to the ULM. (B) Illustrates the functionaluse of the PROTACs as described herein. Briefly, the ULM recognizes andbinds to a specific E3 Ubiquitin Ligase, and the PTM binds and recruitsa target protein bringing it into close proximity to the E3 UbiquitinLigase. Typically, the E3 Ubiquitin Ligase is complexed with an E2ubiquitin-conjugating protein, and either alone or via the E2 proteincatalyzes attachment of ubiquitin (dark circles) to a lysine on thetarget protein via an isopeptide bond. The poly-ubiquitinated protein(far right) is then targeted for degration by the proteosomal machineryof the cell.

DETAILED DESCRIPTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present disclosure. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. All publications, patent applications, patents,figures and other references mentioned herein are expressly incorporatedby reference in their entirety.

Presently described are compositions and methods that relate to thesurprising and unexpected discovery that an E3 Ubiquitin Ligase protein,e.g., cereblon, ubiquitinates a target protein once it and the targetprotein are placed in proximity by a bifunctional or chimeric constructthat binds the E3 Ubiquitin Ligase protein and the target protein.Accordingly the present disclosure provides such compounds andcompositions comprising an E3 Ubiquitin Ligase binding moiety (“ULM”)coupled to a protein target binding moiety (“PTM”), which result in theubiquitination of a chosen target protein, which leads to degradation ofthe target protein by the proteasome (see FIGS. 1A and 1B). The presentdisclosure also provides a library of compositions and the use thereof.

In certain aspects, the present disclosure provides compounds whichcomprise a ligand, e.g., a small molecule ligand (i.e., having amolecular weight of below 2,000, 1,000, 500, or 200 Daltons), which iscapable of binding to a ubiquitin ligase, such as IAP, VHL, MDM2, orcereblon. The compounds also comprise a moiety that is capable ofbinding to target protein, in such a way that the target protein isplaced in proximity to the ubiquitin ligase to effect degradation(and/or inhibition) of that protein. Small molecule can mean, inaddition to the above, that the molecule is non-peptidyl, that is, it isnot generally considered a peptide, e.g., comprises fewer than 4, 3, or2 amino acids. In accordance with the present description, the PTM, ULMor PROTAC molecule can be a small molecule.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The terminology used in thedescription is for describing particular embodiments only and is notintended to be limiting of the invention.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the invention. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

The following terms are used to describe the present invention. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present invention.

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e., “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.”

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anonlimiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The terms “co-administration” and “co-administering” or “combinationtherapy” refer to both concurrent administration (administration of twoor more therapeutic agents at the same time) and time variedadministration (administration of one or more therapeutic agents at atime different from that of the administration of an additionaltherapeutic agent or agents), as long as the therapeutic agents arepresent in the patient to some extent, preferably at effective amounts,at the same time. In certain preferred aspects, one or more of thepresent compounds described herein, are coadministered in combinationwith at least one additional bioactive agent, especially including ananticancer agent. In particularly preferred aspects, theco-administration of compounds results in synergistic activity and/ortherapy, including anticancer activity.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stereoisomers, including optical isomers (enantiomers) and otherstereoisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives, including prodrug and/or deuteratedforms thereof where applicable, in context. Deuterated small moleculescontemplated are those in which one or more of the hydrogen atomscontained in the drug molecule have been replaced by deuterium.

Within its use in context, the term compound generally refers to asingle compound, but also may include other compounds such asstereoisomers, regioisomers and/or optical isomers (including racemicmixtures) as well as specific enantiomers or enantiomerically enrichedmixtures of disclosed compounds. The term also refers, in context toprodrug forms of compounds which have been modified to facilitate theadministration and delivery of compounds to a site of activity. It isnoted that in describing the present compounds, numerous substituentsand variables associated with same, among others, are described. It isunderstood by those of ordinary skill that molecules which are describedherein are stable compounds as generally described hereunder. When thebond is shown, both a double bond and single bond are represented orunderstood within the context of the compound shown and well-known rulesfor valence interactions.

The term “Ubiquitin Ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, cereblonis an E3 Ubiquitin Ligase protein that alone or in combination with anE2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase is involved in polyubiquitination suchthat a second ubiquitin is attached to the first; a third is attached tothe second, and so forth. Polyubiquitination marks proteins fordegradation by the proteasome. However, there are some ubiquitinationevents that are limited to mono-ubiquitination, in which only a singleubiquitin is added by the ubiquitin ligase to a substrate molecule.Mono-ubiquitinated proteins are not targeted to the proteasome fordegradation, but may instead be altered in their cellular location orfunction, for example, via binding other proteins that have domainscapable of binding ubiquitin. Further complicating matters, differentlysines on ubiquitin can be targeted by an E3 to make chains. The mostcommon lysine is Lys48 on the ubiquitin chain. This is the lysine usedto make polyubiquitin, which is recognized by the proteasome.

The term “patient” or “subject” is used throughout the specification todescribe an animal, preferably a human or a domesticated animal, to whomtreatment, including prophylactic treatment, with the compositionsaccording to the present disclosure is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal, including a domesticated animal such as a dog or cat ora farm animal such as a horse, cow, sheep, etc. In general, in thepresent disclosure, the term patient refers to a human patient unlessotherwise stated or implied from the context of the use of the term.

The term “effective” is used to describe an amount of a compound,composition or component which, when used within the context of itsintended use, effects an intended result. The term effective subsumesall other effective amount or effective concentration terms, which areotherwise described or used in the present application.

Compounds and Compositions

In one aspect, the description provides compounds comprising an E3Ubiquitin Ligase binding moiety (“ULM”) that is a cereblon E3 UbiquitinLigase binding moiety (“CLM”). In one embodiment, the CLM is coupled toa chemical linker (L) according to the structure:

L-CLM  (I)

wherein L is a chemical linker group and CLM is a cereblon E3 UbiquitinLigase binding moiety. The number and/or relative positions of themoieties in the compounds illustrated herein is provided by way ofexample only. As would be understood by the skilled artisan, compoundsas described herein can be synthesized with any desired number and/orrelative position of the respective functional moieties.

The terms ULM and CLM are used in their inclusive sense unless thecontext indicates otherwise. For example, the term ULM is inclusive ofall ULMs, including those that bind cereblon (i.e., CLMs). Further, theterm CLM is inclusive of all possible cereblon E3 Ubiquitin Ligasebinding moieties.

In another aspect, the present disclosure provides bifunctional ormultifunctional PROTAC compounds useful for regulating protein activityby inducing the degradation of a target protein. In certain embodiments,the compound comprises a CLM coupled, e.g., linked covalently, directlyor indirectly, to a moiety that binds a target protein (i.e., proteintargeting moiety or “PTM”). In certain embodiments, the CLM and PTM arejoined or coupled via a chemical linker (L). The CLM recognizes thecereblon E3 ubiquitin ligase and the PTM recognizes a target protein andthe interaction of the respective moieties with their targetsfacilitates the degradation of the target protein by placing the targetprotein in proximity to the ubiquitin ligase protein. An exemplarybifunctional compound can be depicted as:

PTM-CLM  (II)

In certain embodiments, the bifunctional compound further comprises achemical linker (“L”). For example, the bifunctional compound can bedepicted as:

PTM-L-CLM  (III)

wherein PTM is a protein/polypeptide targeting moiety, L is a linker,and CLM is a cereblon E3 ligase binding moiety.

In certain embodiments, the compounds as described herein comprisemultiple PTMs (targeting the same or different protein targets),multiple CLMs, one or more ULMs (i.e., moieties that bind specificallyto another E3 Ubiquitin Ligase, e.g., VHL) or a combination thereof. Inany of the aspects of embodiments described herein, the PTMs, CLMs, andULMs can be coupled directly or via one or more chemical linkers or acombination thereof. In additional embodiments, where a compound hasmultiple ULMs, the ULMs can be for the same E3 Ubiquitin Ligase or eachrespective ULM can bind specifically to a different E3 Ubiquitin Ligase.In still further embodiments, where a compound has multiple PTMs, thePTMs can bind the same target protein or each respective PTM can bindspecifically to a different target protein.

In another embodiment, the description provides a compound whichcomprises a plurality of CLMs coupled directly or via a chemical linkermoiety (L). For example, a compound having two CLMs can be depicted as:

CLM-CLM or  (IV)

CLM-L-CLM  (V)

In certain embodiments, where the compound comprises multiple CLMs, theCLMs are identical. In additional embodiments, the compound comprising aplurality of CLMs further comprises at least one PTM coupled to a CLMdirectly or via a chemical linker (L) or both. In certain additionalembodiments, the compound comprising a plurality of CLMs furthercomprises multiple PTMs. In still additional embodiments, the PTMs arethe same or, optionally, different. In still further embodiments,wherein the PTMs are different the respective PTMs may bind the sameprotein target or bind specifically to a different protein target.

In additional embodiments, the description provides a compoundcomprising at least two different CLMs coupled directly or via achemical linker (L) or both. For example, such a compound having twodifferent CLMs can be depicted as:

CLM-CLM′ or  (VI)

CLM-L-CLM′  (VII)

wherein CLM′ indicates a cereblon E3 Ubiquitin Ligase binding moietythat is structurally different from CLM. In certain embodiments, thecompound may comprise a plurality of CLMs and/or a plurality of CLM's.In further embodiments, the compound comprising at least two differentCLMs, a plurality of CLMs, and/or a plurality of CLM's further comprisesat least one PTM coupled to a CLM or a CLM′ directly or via a chemicallinker or both. In any of the embodiments described herein, a compoundcomprising at least two different CLMs can further comprise multiplePTMs. In still additional embodiments, the PTMs are the same or,optionally, different. In still further embodiments, wherein the PTMsare different the respective PTMs may bind the same protein target orbind specifically to a different protein target. In still furtherembodiments, the PTM itself is a ULM or CLM (or ULM′ or CLM′).

In a preferred embodiment, the CLM comprises a moiety that is a ligandof the cereblon E3 Ubiquitin Ligase (CRBN). In certain embodiments, theCLM comprises a chemotype from the “imide” class of molecules. Incertain additional embodiments, the CLM comprises a phthalimido group oran analog or derivative thereof. In still additional embodiments, theCLM comprises a phthalimido-glutarimide group or an analog or derivativethereof. In still other embodiments, the CLM comprises a member of thegroup consisting of thalidomide, lenalidomide, pomalidomide, and analogsor derivatives thereof.

In additional embodiments, the description provides the compounds asdescribed herein including their enantiomers, diastereomers, solvatesand polymorphs, including pharmaceutically acceptable salt formsthereof, e.g., acid and base salt forms.

Exemplary Cereblon Binding and/or Inhibiting Compounds

In one aspect the description provides compounds useful for bindingand/or inhibiting cereblon E3 Ubiquitin Ligase binding moiety. Incertain embodiments, the compound has a chemical structure that includesat least one of (e.g., the compound has a chemical structure selectedfrom the group consisting of):

Neo-Imide Compounds

In one aspect the description provides compounds useful for bindingand/or inhibiting cereblon. In certain embodiments, the compound isselected from the group consisting of chemical structures:

wherein:

-   -   W of Formulas (a) through (e) is independently selected from the        group CH ₂, CHR, C═O, SO₂, NH, cyclopropyl group, cyclobutyl        group, and N-alkyl;    -   W₃ is selected from C or N;    -   X of Formulas (a) through (e) is independently selected from the        group O, S and H₂,    -   Y of Formulas (a) through (e) is independently selected from the        group CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,        N-heterocyclyl, O, and S;    -   Z of Formulas (a) through (e) is independently selected from the        group O, and S or H₂ except that both X and Z cannot be H₂,    -   G and G′ of Formulas (a) through (e) are independently selected        from the group H, alkyl (linear, branched, optionally        substituted), OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl        optionally substituted with R′, and benzyl optionally        substituted with R′;    -   Q1-Q4 of Formulas (a) through (e) represent a carbon C        substituted with a group independently selected from R′, N or        N-oxide;    -   A of Formulas (a) through (e) is independently selected from the        group H, alkyl (linear, branched, optionally substituted),        cycloalkyl, Cl and F;    -   R of Formulas (a) through (e) comprises, but is not limited to:        —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—,        —CR′NR′R″—, (—CR′O)_(n′)R″, -aryl, -hetaryl, -alkyl (linear,        branched, optionally substituted), -cycloalkyl, -heterocyclyl,        —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F,        —Br, —I, —CF3, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″,        —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″,        —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′, —C(C═N—OR′)R″,        —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and —OCF₃R′ and R″ of        Formulas (a) through (e) are independently selected from a bond,        H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, —C(═O)R,        heterocyclyl, each of which is optionally substituted;    -   n′ of Formulas (a) through (e) is an integer from 1-10 (e.g.,        1-4);    -   of Formulas (a) through (e) represents a bond that may be        stereospecific ((R) or (S)) or non-stereospecific;    -   represents a single bond or a double bond;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   Rn comprises 1-4 independent functional groups, optionally        substituted linear or branched alkyl (e.g., a C1-C6 linear or        branched alkyl optionally substituted with one or more halogen,        cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7        aryl)), optionally substituted aryl (e.g., an optionally        substituted C5-C7 aryl), optionally substituted alkyl-aryl        (e.g., an alkyl-aryl comprising at least one of an optionally        substituted C1-C6 alkyl, an optionally substituted C5-C7 aryl,        or combinations thereof), optionally substituted alkoxyl group        (e.g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy;        wherein the alkoxyl may be substituted with one or more halogen,        alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6        cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted

-   -    (e.g., optionally substituted with one or more halogen, alkyl,        haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or        aryl (e.g., C5-C7 aryl)), optionally substituted

-   -    (e.g., optionally substituted with one or more halogen, alkyl,        haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or        aryl (e.g., C5-C7 aryl)), or atoms; and    -   each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6,

Exemplary CLMs

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W of Formulas (a) through (e) is independently selected from the        group CH₂, CHR, C═O, SO₂, NH, N, optionally substituted        cyclopropyl group, optionally substituted cyclobutyl group, and        N-alkyl;    -   W₃ is selected from C or N;    -   X of Formulas (a) through (e) is independently selected from the        group O, S and H₂;    -   Y of Formulas (a) through (e) is independently selected from the        group CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,        N-heterocyclyl, O, and S;    -   Z of Formulas (a) through (e) is independently selected from the        group O, and S or H₂ except that both X and Z cannot be H₂;    -   G and G′ of Formulas (a) through (e) are independently selected        from the group H, alkyl (linear, branched), OH, R′OCOOR,        R′OCONRR″, CH₂-heterocyclyl optionally substituted with R′, and        benzyl optionally substituted with R′;    -   Q1-Q4 of Formulas (a) through (e) represent a carbon C        substituted with a group independently selected from R′, N or        N-oxide;    -   A of Formulas (a) through (e) is independently selected from the        group H, alkyl (linear, branched, optionally substituted),        cycloalkyl, Cl and F;    -   R of Formulas (a) through (e) comprises, but is not limited to:        —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—,        —CR′NR′R″—, (—CR′O)_(n′)R″, -aryl, -hetaryl, -alkyl (linear,        branched, optionally substituted), -cycloalkyl, -heterocyclyl,        —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F,        —Br, —I, —CF3, —CN, —NR′SO2NR′R″, —NR′CONR′R″, —CONR′COR″,        —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″,        —NR′C(═C—NO2)NR′R″, —SO2NR′COR″, —NO2, —CO2R′, —C(C═N—OR′)R″,        —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF5 and —OCF3    -   R′ and R″ of Formulas (a) through (e) are independently selected        from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl,        heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally        substituted;    -   n′ of Formulas (a) through (e) is an integer from 1-10 (e.g.,        1-4);    -   represents a single bond or a double bond;    -   of Formulas (a) through (e) represents a bond that may be        stereospecific ((R) or (S)) or non-stereospecific;    -   Rn comprises 1-4 independent functional groups, optionally        substituted linear or branched alkyl (e.g., a C1-C6 linear or        branched alkyl optionally substituted with one or more halogen,        cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7        aryl)), optionally substituted aryl (e.g., an optionally        substituted C5-C7 aryl), optionally substituted alkyl-aryl        (e.g., an alkyl-aryl comprising at least one of an optionally        substituted C1-C6 alkyl, an optionally substituted C5-C7 aryl,        or combinations thereof), optionally substituted alkoxyl group        (e.g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy;        wherein the alkoxyl may be substituted with one or more halogen,        alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6        cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted

-   -    (e.g., optionally substituted with one or more halogen, alkyl,        haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or        aryl (e.g., C5-C7 aryl)), optionally substituted

-   -    (e.g., optionally substituted with one or more halogen, alkyl,        haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or        aryl (e.g., C5-C7 aryl)), or atoms; and    -   each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6.

In certain embodiments described herein, the CLM or ULM comprises achemical structure selected from the group:

wherein:

-   -   W of Formula (g) is independently selected from the group CH₂,        C═O, NH, and N-alkyl;    -   R of Formula (g) is independently selected from a H, methyl,        alkyl (e.g., a or C1-C6 alkyl (linear, branched, optionally        substituted));    -   of Formula (g) represents a bond that may be stereospecific ((R)        or (S)) or non-stereospecific; and    -   Rn comprises 1-4 independent functional groups, optionally        substituted linear or branched alkyl (e.g., a C1-C6 linear or        branched alkyl optionally substituted with one or more halogen,        cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7        aryl)), optionally substituted aryl (e.g., an optionally        substituted C5-C7 aryl), optionally substituted alkyl-aryl        (e.g., an alkyl-aryl comprising at least one of an optionally        substituted C1-C6 alkyl, an optionally substituted C5-C7 aryl,        or combinations thereof), optionally substituted alkoxyl group        (e.g., a methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy;        wherein the alkoxyl may be substituted with one or more halogen,        alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6        cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted

-   -    (e.g., optionally substituted with one or more halogen, alkyl,        haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or        aryl (e.g., C5-C7 aryl)), optionally substituted

-   -    (e.g., optionally substituted with one or more halogen, alkyl,        haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or        aryl (e.g., C5-C7 aryl)), or atoms.

In any of the embodiments described herein, the W, X, Y, Z, G, G′, R,R′, R″, Q1-Q4, A, and Rn of Formulas (a) through (g) can independentlybe covalently coupled to a linker and/or a linker to which is attachedone or more PTM, ULM, CLM or CLM′ groups.

More specifically, non-limiting examples of CLMs include those shownbelow as well as those “hybrid” molecules that arise from thecombination of 1 or more of the different features shown in themolecules below.

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “alkyl” shall mean within its context a linear, branch-chainedor cyclic fully saturated hydrocarbon radical or alkyl group, preferablya C₁-C₁₀, more preferably a C₁-C₆, alternatively a C1-C3 alkyl group,which may be optionally substituted. Examples of alkyl groups aremethyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl andcyclohexyl, among others. In certain embodiments, the alkyl group isend-capped with a halogen group (At, Br, Cl, F, or I). In certainpreferred embodiments, compounds according to the present disclosurewhich may be used to covalently bind to dehalogenase enzymes. Thesecompounds generally contain a side chain (often linked through apolyethylene glycol group) which terminates in an alkyl group which hasa halogen substituent (often chlorine or bromine) on its distal endwhich results in covalent binding of the compound containing such amoiety to the protein.

The term “Alkoxy” refers to an alkyl group singularly bonded to oxygen.

The term “Alkenyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C═Cbond.

The term “Alkynyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one CC bond.

The term “alkylene” when used, refers to a —(CH₂)_(n)— group (n is aninteger generally from 0-6), which may be optionally substituted. Whensubstituted, the alkylene group preferably is substituted on one or moreof the methylene groups with a C₁-C₆ alkyl group (including acyclopropyl group or a t-butyl group), but may also be substituted withone or more halo groups, preferably from 1 to 3 halo groups or one ortwo hydroxyl groups, O—(C₁-C₆ alkyl) groups or amino acid sidechains asotherwise disclosed herein. In certain embodiments, an alkylene groupmay be substituted with a urethane or alkoxy group (or other group)which is further substituted with a polyethylene glycol chain (of from 1to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to whichis substituted (preferably, but not exclusively on the distal end of thepolyethylene glycol chain) an alkyl chain substituted with a singlehalogen group, preferably a chlorine group. In still other embodiments,the alkylene (often, a methylene) group, may be substituted with anamino acid sidechain group such as a sidechain group of a natural orunnatural amino acid, for example, alanine, β-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

The term “unsubstituted” shall mean substituted only with hydrogenatoms. A range of carbon atoms which includes C₀ means that carbon isabsent and is replaced with H. Thus, a range of carbon atoms which isC₀-C₆ includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for C₀, H standsin place of carbon.

The term “substituted” or “optionally substituted” shall meanindependently (i.e., where more than substituent occurs, eachsubstituent is independent of another substituent) one or moresubstituents (independently up to five substitutents, preferably up tothree substituents, often 1 or 2 substituents on a moiety in a compoundaccording to the present disclosure and may include substituents whichthemselves may be further substituted) at a carbon (or nitrogen)position anywhere on a molecule within context, and includes assubstituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO₂),halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl,especially a methyl group such as a trifluoromethyl), an alkyl group(preferably, C₁-C₁₀, more preferably, C₁-C₆), aryl (especially phenyland substituted phenyl for example benzyl or benzoyl), alkoxy group(preferably, C₁-C₆ alkyl or aryl, including phenyl and substitutedphenyl), thioether (C₁-C₆ alkyl or aryl), acyl (preferably, C₁-C₆ acyl),ester or thioester (preferably, C₁-C₆ alkyl or aryl) including alkyleneester (such that attachment is on the alkylene group, rather than at theester function which is preferably substituted with a C₁-C₆ alkyl oraryl group), preferably, C₁-C₆ alkyl or aryl, halogen (preferably, F orCl), amine (including a five- or six-membered cyclic alkylene amine,further including a C₁-C₆ alkyl amine or a C₁-C₆ dialkyl amine whichalkyl groups may be substituted with one or two hydroxyl groups) or anoptionally substituted —N(C₀-C₆ alkyl)C(O)(O—C₁-C₆ alkyl) group (whichmay be optionally substituted with a polyethylene glycol chain to whichis further bound an alkyl group containing a single halogen, preferablychlorine substituent), hydrazine, amido, which is preferably substitutedwith one or two C₁-C₆ alkyl groups (including a carboxamide which isoptionally substituted with one or two C₁-C₆ alkyl groups), alkanol(preferably, C₁-C₆ alkyl or aryl), or alkanoic acid (preferably, C₁-C₆alkyl or aryl). Substituents according to the present disclosure mayinclude, for example —SiR_(1sub)R_(2sub)R_(3sub) groups where each ofR_(1sub) and R_(2sub) is as otherwise described herein and R_(3sub) is Hor a C₁-C₆ alkyl group, preferably R_(1sub), R_(2sub), R_(3sub) in thiscontext is a C₁-C₃ alkyl group (including an isopropyl or t-butylgroup). Each of the above-described groups may be linked directly to thesubstituted moiety or alternatively, the substituent may be linked tothe substituted moiety (preferably in the case of an aryl or heteroarylmoiety) through an optionally substituted —(CH₂)_(m)— or alternativelyan optionally substituted —(OCH₂)_(m)—, —(OCH₂CH₂)_(m)— or—(CH₂CH₂O)_(m)— group, which may be substituted with any one or more ofthe above-described substituents. Alkylene groups —(CH₂)_(m)— or—(CH₂)_(n)— groups or other chains such as ethylene glycol chains, asidentified above, may be substituted anywhere on the chain. Preferredsubstitutents on alkylene groups include halogen or C₁-C₆ (preferablyC₁-C₃) alkyl groups, which may be optionally substituted with one or twohydroxyl groups, one or two ether groups (O—C₁-C₆ groups), up to threehalo groups (preferably F), or a sidechain of an amino acid as otherwisedescribed herein and optionally substituted amide (preferablycarboxamide substituted as described above) or urethane groups (oftenwith one or two C₀-C₆ alkyl substitutents, which group(s) may be furthersubstituted). In certain embodiments, the alkylene group (often a singlemethylene group) is substituted with one or two optionally substitutedC₁-C₆ alkyl groups, preferably C₁-C₄ alkyl group, most often methyl orO-methyl groups or a sidechain of an amino acid as otherwise describedherein. In the present disclosure, a moiety in a molecule may beoptionally substituted with up to five substituents, preferably up tothree substituents. Most often, in the present disclosure, moietieswhich are substituted are substituted with one or two substituents.

The term “substituted” (each substituent being independent of any othersubstituent) shall also mean within its context of use C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, amido, carboxamido, sulfone, includingsulfonamide, keto, carboxy, C₁-C₆ ester (oxyester or carbonylester),C₁-C₆keto, urethane —O—C(O)—NR_(1sub)R_(2sub) or—N(R_(1sub))—C(O)—O—R_(1sub), nitro, cyano and amine (especiallyincluding a C₁-C₆ alkylene-NR_(1sub)R_(2sub), a mono- or di-C₁-C₆ alkylsubstituted amines which may be optionally substituted with one or twohydroxyl groups). Each of these groups contain unless otherwiseindicated, within context, between 1 and 6 carbon atoms. In certainembodiments, preferred substituents will include for example, —NH—,—NHC(O)—, —O—, ═O, —(CH₂)_(m)— (here, m and n are in context, 1, 2, 3,4, 5 or 6), —S—, —S(O)—, SO₂— or —NH—C(O)—NH—, —(CH₂)_(n)OH,—(CH₂)_(n)SH, —(CH₂)_(n)COOH, C₁-C₆ alkyl, —(CH₂)_(n)—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)—(C₁-C₆ alkyl), —(CH₂)_(n)C(O)—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)O—(C₁-C₆ alkyl), —(CH₂)_(n)NHC(O)—R_(1sub),—(CH₂)_(n)C(O)—NR_(1sub)R_(2sub), —(OCH₂)_(n)H, —(CH₂O)_(n)COOH, C₁-C₆alkyl, —(OCH₂)_(n)—(C₁-C₆ alkyl), —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),—(OCH₂)_(n)NHC(O)—R_(1sub), —(CH₂O)_(n)C(O)—NR_(1sub)R_(2sub),—S(O)₂—R_(S), —S(O)—R_(S) (R_(S) is C₁-C₆ alkyl or a—(CH₂)_(m)—NR_(1sub)R_(2sub) group), NO₂, CN or halogen (F, Cl, Br, I,preferably F or Cl), depending on the context of the use of thesubstituent. R_(1sub) and R_(2sub) are each, within context, H or aC₁-C₆ alkyl group (which may be optionally substituted with one or twohydroxyl groups or up to three halogen groups, preferably fluorine). Theterm “substituted” shall also mean, within the chemical context of thecompound defined and substituent used, an optionally substituted aryl orheteroaryl group or an optionally substituted heterocyclic group asotherwise described herein. Alkylene groups may also be substituted asotherwise disclosed herein, preferably with optionally substituted C₁-C₆alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl ispreferred, thus providing a chiral center), a sidechain of an amino acidgroup as otherwise described herein, an amido group as describedhereinabove, or a urethane group O—C(O)—NR_(1sub)R_(2sub) group whereR_(1sub) and R_(2sub) are as otherwise described herein, althoughnumerous other groups may also be used as substituents. Variousoptionally substituted moieties may be substituted with 3 or moresubstituents, preferably no more than 3 substituents and preferably with1 or 2 substituents. It is noted that in instances where, in a compoundat a particular position of the molecule substitution is required(principally, because of valency), but no substitution is indicated,then that substituent is construed or understood to be H, unless thecontext of the substitution suggests otherwise.

The term “aryl” or “aromatic”, in context, refers to a substituted (asotherwise described herein) or unsubstituted monovalent aromatic radicalhaving a single ring (e.g., benzene, phenyl, benzyl) or condensed rings(e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound tothe compound according to the present disclosure at any available stableposition on the ring(s) or as otherwise indicated in the chemicalstructure presented. Other examples of aryl groups, in context, mayinclude heterocyclic aromatic ring systems, “heteroaryl” groups havingone or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic)such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine,pyrimidine, pyrazine, triazole, oxazole or fused ring systems such asindole, quinoline, indolizine, azaindolizine, benzofurazan, etc., amongothers, which may be optionally substituted as described above. Amongthe heteroaryl groups which may be mentioned include nitrogen-containingheteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine,pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine,tetrazole, indole, isoindole, indolizine, azaindolizine, purine,indazole, quinoline, dihydroquinoline, tetrahydroquinoline,isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine,acridine, phenanthridine, carbazole, carbazoline, pyrimidine,phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine,pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromaticheterocycles such as thiophene and benzothiophene; oxygen-containingaromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuranand isobenzofuran; and aromatic heterocycles comprising 2 or more heteroatoms selected from among nitrogen, sulfur and oxygen, such as thiazole,thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole, among others, all of whichmay be optionally substituted.

The term “substituted aryl” refers to an aromatic carbocyclic groupcomprised of at least one aromatic ring or of multiple condensed ringsat least one of which being aromatic, wherein the ring(s) aresubstituted with one or more substituents. For example, an aryl groupcan comprise a substituent(s) selected from: —(CH₂)_(n)OH,—(CH₂)_(n)O—(C₁-C₆)alkyl, —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl,—(CH₂)_(n)—C(O)(C₀-C₆) alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,—(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl) aminewherein the alkyl group on the amine is optionally substituted with 1 or2 hydroxyl groups or up to three halo (preferably F, C1) groups, OH,COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group(each of which may be substituted in ortho-, meta- and/or para-positionsof the phenyl ring, preferably para-), an optionally substituted phenylgroup (the phenyl group itself is preferably substituted with a linkergroup attached to a PTM group, including a ULM group), and/or at leastone of F, Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (inortho-, meta- and/or para-positions of the phenyl ring, preferablypara-), a naphthyl group, which may be optionally substituted, anoptionally substituted heteroaryl, preferably an optionally substitutedisoxazole including a methylsubstituted isoxazole, an optionallysubstituted oxazole including a methylsubstituted oxazole, an optionallysubstituted thiazole including a methyl substituted thiazole, anoptionally substituted isothiazole including a methyl substitutedisothiazole, an optionally substituted pyrrole including amethylsubstituted pyrrole, an optionally substituted imidazole includinga methylimidazole, an optionally substituted benzimidazole ormethoxybenzylimidazole, an optionally substituted oximidazole ormethyloximidazole, an optionally substituted diazole group, including amethyldiazole group, an optionally substituted triazole group, includinga methylsubstituted triazole group, an optionally substituted pyridinegroup, including a halo-(preferably, F) or methylsubstitutedpyridinegroup or an oxapyridine group (where the pyridine group is linked to thephenyl group by an oxygen), an optionally substituted furan, anoptionally substituted benzofuran, an optionally substituteddihydrobenzofuran, an optionally substituted indole, indolizine orazaindolizine (2, 3, or 4-azaindolizine), an optionally substitutedquinoline, and combinations thereof.

“Carboxyl” denotes the group —C(O)OR, where R is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl, whereas these generic substituents have meanings which areidentical with definitions of the corresponding groups defined herein.

The term “heteroaryl” or “hetaryl” can mean but is in no way limited toan optionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure:

wherein

-   -   S^(c) is CHR^(SS), NR^(URE); or O;    -   R^(HET) is H, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(SS) is H, CN, NO₂, halo (preferably F or Cl), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups), optionally        substituted O—(C₁-C₆ alkyl) (preferably substituted with one or        two hydroxyl groups or up to three halo groups) or an optionally        substituted —C(O)(C₁-C₆ alkyl) (preferably substituted with one        or two hydroxyl groups or up to three halo groups);    -   R^(URE) is H, a C₁-C₆ alkyl (preferably H or C₁-C₃ alkyl) or a        —C(O)(C₁-C₆ alkyl), each of which groups is optionally        substituted with one or two hydroxyl groups or up to three        halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) is N or C—R^(YC), where R^(YC) is H, OH, CN, NO₂, halo        (preferably Cl or F), optionally substituted C₁-C₆ alkyl        (preferably substituted with one or two hydroxyl groups or up to        three halo groups (e.g. CF₃), optionally substituted O(C₁-C₆        alkyl) (preferably substituted with one or two hydroxyl groups        or up to three halo groups) or an optionally substituted        acetylenic group —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl        group (preferably C₁-C₃ alkyl).

The term “Heterocycle” refers to a cyclic group which contains at leastone heteroatom, e.g., N, O or S, and may be aromatic (heteroaryl) ornon-aromatic. Thus, the heteroaryl moieties are subsumed under thedefinition of heterocycle, depending on the context of its use.Exemplary heteroaryl groups are described hereinabove.

Exemplary heterocyclics include: azetidinyl, benzimidazolyl,1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl,benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl,dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane,1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl,imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl,oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl,N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl,pyrazolinyl, pyridyl, pyrimidinyl, pyrrolinyl, pyrrolyl, quinolinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinylthienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, thianeamong others.

Heterocyclic groups can be optionally substituted with a member selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SOaryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, oxo (═O), and—SO₂-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Examples of nitrogen heterocycles andheteroaryls include, but are not limited to, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like aswell as N-alkoxy-nitrogen containing heterocycles. The term“heterocyclic” also includes bicyclic groups in which any of theheterocyclic rings is fused to a benzene ring or a cyclohexane ring oranother heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, and the like).

The term “cycloalkyl” can mean but is in no way limited to univalentgroups derived from monocyclic or polycyclic alkyl groups orcycloalkanes, as defined herein, e.g., saturated monocyclic hydrocarbongroups having from three to twenty carbon atoms in the ring, including,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. The term “substituted cycloalkyl” can mean butis in no way limited to a monocyclic or polycyclic alkyl group and beingsubstituted by one or more substituents, for example, amino, halogen,alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,mercapto or sulfo, whereas these generic substituent groups havemeanings which are identical with definitions of the correspondinggroups as defined in this legend.

The term “hydrocarbyl” shall mean a compound which contains carbon andhydrogen and which may be fully saturated, partially unsaturated oraromatic and includes aryl groups, alkyl groups, alkenyl groups andalkynyl groups.

The term “lower alkyl” refers to methyl, ethyl or propyl

The term “lower alkoxy” refers to methoxy, ethoxy or propoxy.

More specifically, non-limiting examples of CLMs include those shownbelow as well as “hybrid” molecules or compounds that arise fromcombining 1 or more features of the following compounds:

wherein:

-   -   W is independently selected from the group CH₂, CHR, C═O, SO₂,        NH, and N-alkyl;    -   R¹ is selected from the group absent, H, CH, CN, C₁-C₃ alkyl;    -   R² is H or a C₁-C₃ alkyl;    -   R³ is selected from H, alkyl, substituted alkyl, alkoxy,        substituted alkoxy;    -   R⁴ is methyl or ethyl;    -   R⁵ is H or halo;    -   R⁶ is H or halo;    -   R of the CLM is H;    -   R′ is H or an attachment point for a PTM, a PTM′, a chemical        linker group (L), a ULM, a CLM, a CLM′,    -   Q1 and Q2 are each independently C or N substituted with a group        independently selected from H or C₁-C₃ alkyl;    -   is a single or double bond; and    -   Rn comprises a functional group or an atom.

In any of the embodiments described herein, the W, R¹, R², Q₁, Q₂, Q₃,Q₄, and Rn can independently be covalently coupled to a linker and/or alinker to which is attached one or more PTM, ULM, ULM′, CLM or CLM′groups.

In any of the embodiments described herein, the R¹, R², Q₁, Q₂, Q₃, Q₄,and Rn can independently be covalently coupled to a linker and/or alinker to which is attached one or more PTM, ULM, ULM′, CLM or CLM′groups.

In any of the embodiments described herein, the Q₁, Q₂, Q₃, Q₄, and Rncan independently be covalently coupled to a linker and/or a linker towhich is attached one or more PTM, ULM, ULM′, CLM or CLM′ groups.

In any aspect or embodiment described herein, R_(n) is modified to becovalently joined to the linker group (L), a PTM, a ULM, a second CLMhaving the same chemical structure as the CLM, a CLM′, a second linker,or any multiple or combination thereof.

Exemplary Linkers

In certain embodiments, the compounds as described herein include one ormore CLMs chemically linked or coupled to one or more PTMs (e.g., PTMand/or PTM′), ULMs (e.g., ULM, ULM′, and/or CLM′) via a chemical linker(L). In certain embodiments, the linker group L is a group comprisingone or more covalently connected structural units (e.g., -A^(L) ₁ . . .(A^(L))_(q)- or -(A^(L))_(q)-), wherein A₁ is a group coupled to PTM,and Aq is a group coupled to at least one of a ULM, a ULM′, a CLM, aCLM′, or a combination thereof. In certain embodiments, A^(L) ₁ links aCLM or CLM′ directly to another ULM, PTM, or combination thereof. Inother embodiments, A^(L) ₁ links a CLM or CLM′ indirectly to anotherULM, PTM, or combination thereof through A_(q).

In any aspect or embodiment described herein, the linker group L is abond or a chemical linker group represented by the formula-(A^(L))_(q)-, wherein A is a chemical moiety and q is an integer from1-100, and wherein L is covalently bound to the PTM and the ULM, andprovides for sufficient binding of the PTM to the protein target and theULM to an E3 ubiquitin ligase to result in target proteinubiquitination.

In certain embodiments, the linker group is -(A^(L))_(q)-, wherein

-   -   (A^(L))_(q)- is a group which is connected to at least one of a        ULM moiety, a PTM moiety, or a combination thereof;    -   q of the linker is an integer greater than or equal to 1;    -   each A^(L) is independently selected from the group consisting        of a bond, CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3), SO₂NR¹³,        SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO,        CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1),        NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4),        C₃₋₁₁ cycloalkyl optionally substituted with 0-6 R^(L1) and/or        R^(L2) groups, C₅₋₁₃ spirocycloalkyl optionally substituted with        0-9 R^(L1) and/or R^(L2) groups, C₃₋₁₁heterocyclyl optionally        substituted with 0-6 R^(L1) and/or R^(L2) groups, C₅₋₁₃        spiroheterocycloalkyl optionally substituted with 0-8 R^(L1)        and/or R^(L2) groups, aryl optionally substituted with 0-6        R^(L1) and/or R^(L2) groups, heteroaryl optionally substituted        with 0-6 R^(L1) and/or R^(L2) groups, where R^(L1) or R^(L2),        each independently are optionally linked to other groups to form        cycloalkyl and/or heterocyclyl moiety, optionally substituted        with 0-4 R^(L5) groups; and    -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈ alkyl, OC₁₋₈ alkyl, SC₁₋₈ alkyl,        NHC₁₋₈ alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈cycloalkyl, SC₁₋₈ cycloalkyl, NHC₁₋₈        cycloalkyl, N(C₁₋₈ cycloalkyl)₂, N(C₁₋₈ cycloalkyl)(C₁₋₈alkyl),        OH, NH₂, SH, SO₂C₁₋₈ alkyl, P(O)(OC₁₋₈ alkyl)(C₁₋₈ alkyl),        P(O)(OC₁₋₈ alkyl)₂, CC—C₁₋₈alkyl, CCH, CH═CH(C₁₋₈ alkyl), C(C₁₋₈        alkyl)═CH(C₁₋₈ alkyl), C(C₁₋₈ alkyl)═C(C₁₋₈ alkyl)₂, Si(OH)₃,        Si(C₁₋₈ alkyl)₃, Si(OH)(C₁₋₈ alkyl)₂, COC₁₋₈ alkyl, CO₂H,        halogen, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅, SO₂NHC₁₋₈ alkyl,        SO₂N(C₁₋₈ alkyl)₂, SONHC₁₋₈ alkyl, SON(C₁₋₈ alkyl)₂, CONHC₁₋₈        alkyl, CON(C₁₋₈ alkyl)₂, N(C₁₋₈ alkyl)CONH(C₁₋₈ alkyl), N(C₁₋₈        alkyl)CON(C₁₋₈alkyl)₂, NHCONH(C₁₋₈ alkyl), NHCON(C₁₋₈ alkyl)₂,        NHCONH₂, N(C₁₋₈ alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈ alkyl) SO₂N(C₁₋₈        alkyl)₂, NH SO₂NH(C₁₋₈ alkyl), NH SO₂N(C₁₋₈ alkyl)₂, NH SO₂NH₂.

In certain embodiments, q of the linker is an integer greater than orequal to 0. In certain embodiments, q is an integer greater than orequal to 1.

In certain embodiments, e.g., where q is greater than 2, A^(L) _(q) is agroup which is connected to a ULM or ULM′ moiety (such as CLM or CLM′),and A^(L) ₁ and A^(L) _(q) are connected via structural units of thelinker (L).

In certain embodiments, e.g., where q of the linker is 2, A^(L) _(q) isa group which is connected to A^(L) ₁ and to a ULM or a ULM′ moiety(such as CLM or CLM′).

In certain embodiments, e.g., where q of the linker is 1, the structureof the linker group L is -A^(L) ₁, and A^(L) ₁ is a group which isconnected to a ULM or ULM′ moiety (such as CLM or CLM′) and a PTMmoiety.

In certain embodiments, the linker (L) comprises a group represented bya general structure selected from the group consisting of:

-   -   —NR(CH₂)_(n)-(lower alkyl)-, —NR(CH₂)_(n)-(lower alkoxyl)-,        —NR(CH₂)_(n)-(lower alkoxyl)-OCH₂—, —NR(CH₂)_(n)-(lower        alkoxyl)-(lower alkyl)-OCH₂—, —NR(CH₂)_(n)-(cycloalkyl)-(lower        alkyl)-OCH₂—, —NR(CH₂)_(n)-(hetero cycloalkyl)-,        —NR(CH₂CH₂O)_(n)-(lower alkyl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(hetero        cycloalkyl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-Aryl-O—CH₂—,        —NR(CH₂CH₂O)_(n)-(hetero aryl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(cyclo        alkyl)-O-(hetero aryl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(cyclo        alkyl)-O-Aryl-O—CH₂—, —NR(CH₂CH₂O)_(n)-(lower        alkyl)-NH-Aryl-O—CH₂—, —NR(CH₂CH₂O)_(n)-(lower        alkyl)-O-Aryl-CH₂, —NR(CH₂CH₂O)_(n)-cycloalkyl-O-Aryl-,        —NR(CH₂CH₂O)_(n)-cycloalkyl-O-(heteroaryl)1-,        —NR(CH₂CH₂)_(n)-(cycloalkyl)-O-(heterocycle)-CH₂,        —NR(CH₂CH₂)_(n)-(heterocycle)-(heterocycle)-CH₂,        —N(R1R2)-(heterocycle)-CH₂; where    -   n of the linker can be 0 to 10;    -   R of the linker can be H, lower alkyl;    -   R1 and R2 of the linker can form a ring with the connecting N.

In certain embodiments, the A^(L) group is represented by a generalstructure selected from the group consisting of:

-   —N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-,-   —O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-,-   —O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;-   —N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;-   —(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;-   —(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-;

wherein

-   -   m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3,        4, 5, 6; 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;    -   when the number is zero, there is no N—O or O—O bond    -   R of the linker is H, methyl and ethyl;    -   X of the linker is H and F

-   -   where m of the linker can be 2, 3, 4, 5;

where each n and m of the linker can independently be 0, 1, 2, 3, 4, 5,6.

In any aspect or embodiment described herein, the A^(L) group isselected from the group consisting of:

wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, or6.

In any aspect or embodiment described herein, A^(L) group is selectedfrom the group consisting of:

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In any aspect or embodiment described herein, the A^(L) group isselected from the group consisting of:

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties:

wherein:

-   -   W^(L1) and W^(L2) are each independently absent, a 4-8 membered        ring with 0-4 heteroatoms, optionally substituted with R^(Q),        each R^(Q) is independently a H, halo, OH, CN, CF₃, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), or 2 R^(Q) groups        taken together with the atom they are attached to, form a 4-8        membered ring system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; or C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties:

wherein:

-   -   W^(L1) and W^(L2) are each independently absent, aryl,        heteroaryl, cyclic, heterocyclic, C₁₋₆ alkyl and optionally one        or more C atoms are replaced with O, C₁₋₆ alkene and optionally        one or more C atoms are replaced with O, C₁₋₆ alkyne and        optionally one or more C atoms are replaced with O, bicyclic,        biaryl, biheteroaryl, or biheterocyclic, each optionally        substituted with R^(Q), each R^(Q) is independently a H, halo,        OH, CN, CF₃, hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁-C₆ alkyl (linear, branched, optionally substituted), C₁-C₆        alkoxy (linear, branched, optionally substituted), OC₁₋₃ alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 4-8 membered ring system        containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, NR^(YL1), O, S, NR^(YL2),        CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   Q^(L) is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally bridged, optionally substituted with 0-6        R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), or 2 R^(Q) groups taken together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   R^(YL1), R^(YL2) are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker group is optionally substituted(poly)ethyleneglycol having between 1 and about 100 ethylene glycolunits, between about 1 and about 50 ethylene glycol units, between 1 andabout 25 ethylene glycol units, between about 1 and 10 ethylene glycolunits, between 1 and about 8 ethylene glycol units and 1 and 6 ethyleneglycol units, between 2 and 4 ethylene glycol units, or optionallysubstituted alkyl groups interdispersed with optionally substituted, O,N, S, P or Si atoms. In certain embodiments, the linker is substitutedwith an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. Incertain embodiments, the linker may be asymmetric or symmetrical.

In any of the embodiments of the compounds described herein, the linkergroup may be any suitable moiety as described herein. In one embodiment,the linker is a substituted or unsubstituted polyethylene glycol groupranging in size from about 1 to about 12 ethylene glycol units, between1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycolunits, between about 2 and 5 ethylene glycol units, between about 2 and4 ethylene glycol units.

In another embodiment, the present disclosure is directed to a compoundwhich comprises a PTM group, which binds to a target protein orpolypeptide, which is ubiquitinated by an ubiquitin ligase and ischemically linked directly to the ULM group (such as CLM) or through alinker moiety L, or PTM is alternatively a ULM′ group (such as CLM′)which is also a ubiquitin ligase binding moiety, which may be the sameor different than the ULM group as described above and is linkeddirectly to the ULM group directly or through the linker moiety; and Lis a linker moiety as described above which may be present or absent andwhich chemically (covalently) links ULM to PTM, or a pharmaceuticallyacceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

In certain embodiments, the linker group L is a group comprising one ormore covalently connected structural units independently selected fromthe group consisting of:

The X is selected from the group consisting of O, N, S, S(O) and SO₂; nis integer from 1 to 5; R^(L1) is hydrogen or alkyl,

is a mono- or bicyclic aryl or heteroaryl optionally substituted with1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy,alkoxy or cyano;

is a mono- or bicyclic cycloalkyl or a heterocycloalkyl optionallysubstituted with 1-3 substituents selected from alkyl, halogen,haloalkyl, hydroxy, alkoxy or cyano; and the phenyl ring fragment can beoptionally substituted with 1, 2 or 3 substituents selected from thegroup consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy andcyano. In an embodiment, the linker group L comprises up to 10covalently connected structural units, as described above.

Although the ULM group and PTM group may be covalently linked to thelinker group through any group which is appropriate and stable to thechemistry of the linker, in preferred aspects of the present disclosure,the linker is independently covalently bonded to the ULM group and thePTM group preferably through an amide, ester, thioester, keto group,carbamate (urethane), carbon or ether, each of which groups may beinserted anywhere on the ULM group and PTM group to provide maximumbinding of the ULM group on the ubiquitin ligase and the PTM group onthe target protein to be degraded. (It is noted that in certain aspectswhere the PTM group is a ULM group, the target protein for degradationmay be the ubiquitin ligase itself). In certain preferred aspects, thelinker may be linked to an optionally substituted alkyl, alkylene,alkene or alkyne group, an aryl group or a heterocyclic group on the ULMand/or PTM groups.

In additional embodiments, q is an integer from 1 to 100, 1 to 90, 1 to80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.

In certain embodiments, the linker (L) is selected from the groupconsisting of:

In additional embodiments, the linker group is optionally substituted(poly)ethyleneglycol having between 1 and about 100 ethylene glycolunits, between about 1 and about 50 ethylene glycol units, between 1 andabout 25 ethylene glycol units, between about 1 and 10 ethylene glycolunits, between 1 and about 8 ethylene glycol units and 1 and 6 ethyleneglycol units, between 2 and 4 ethylene glycol units, or optionallysubstituted alkyl groups interdispersed with optionally substituted, O,N, S, P or Si atoms. In certain embodiments, the linker is substitutedwith an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. Incertain embodiments, the linker may be asymmetric or symmetrical.

In any of the embodiments of the compounds described herein, the linkergroup may be any suitable moiety as described herein. In one embodiment,the linker is a substituted or unsubstituted polyethylene glycol groupranging in size from about 1 to about 12 ethylene glycol units, between1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycolunits, between about 2 and 5 ethylene glycol units, between about 2 and4 ethylene glycol units.

Although the CLM (or ULM) group and PTM group may be covalently linkedto the linker group through any group which is appropriate and stable tothe chemistry of the linker, in preferred aspects of the presentdisclosure, the linker is independently covalently bonded to the CLMgroup and the PTM group preferably through an amide, ester, thioester,keto group, carbamate (urethane), carbon or ether, each of which groupsmay be inserted anywhere on the CLM group and PTM group to providemaximum binding of the CLM group on the ubiquitin ligase and the PTMgroup on the target protein to be degraded. (It is noted that in certainaspects where the PTM group is a ULM group, the target protein fordegradation may be the ubiquitin ligase itself). In certain preferredaspects, the linker may be linked to an optionally substituted alkyl,alkylene, alkene or alkyne group, an aryl group or a heterocyclic groupon the CLM and/or PTM groups.

In certain embodiments, “L” can be linear chains with linear atoms from4 to 24, the carbon atom in the linear chain can be substituted withoxygen, nitrogen, amide, fluorinated carbon, etc., such as thefollowing:

In certain embodiments, “L” can be nonlinear chains, and can bealiphatic or aromatic or heteroaromatic cyclic moieties, some examplesof “L” include but not be limited to the following:

wherein:

-   -   ‘X” in above structures can be linear chain with atoms ranging        from 2 to 14, and the mentioned chain can contain heteroatoms        such as oxygen; and    -   “Y” in above structures can be O, N, S(O)_(n) (n=0, 1, 2).

Exemplary PTMs

In preferred aspects of the present disclosure, the PTM group is agroup, which binds to target proteins. Targets of the PTM group arenumerous in kind and are selected from proteins that are expressed in acell such that at least a portion of the sequences is found in the celland may bind to a PTM group. The term “protein” includes oligopeptidesand polypeptide sequences of sufficient length that they can bind to aPTM group according to the present disclosure. Any protein in aeukaryotic system or a microbial system, including a virus, bacteria orfungus, as otherwise described herein, are targets for ubiquitinationmediated by the compounds according to the present disclosure.Preferably, the target protein is a eukaryotic protein. In certainaspects, the protein binding moiety is a haloalkane (preferably a C₁-C₁₀alkyl group which is substituted with at least one halo group,preferably a halo group at the distal end of the alkyl group, i.e., awayfrom the linker or CLM group), which may covalently bind to adehalogenase enzyme in a patient or subject or in a diagnostic assay.

PTM groups according to the present disclosure include, for example,include any moiety which binds to a protein specifically (binds to atarget protein) and includes the following non-limiting examples ofsmall molecule target protein moieties: Hsp90 inhibitors, kinaseinhibitors, androgen receptor inhibitors, HDM2 & MDM2 inhibitors,compounds targeting Human BET Bromodomain-containing proteins, HDACinhibitors, human lysine methyltransferase inhibitors, angiogenesisinhibitors, nuclear hormone receptor compounds, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR),among numerous others. The compositions described below exemplify someof the members of these nine types of small molecule target proteinbinding moieties. Such small molecule target protein binding moietiesalso include pharmaceutically acceptable salts, enantiomers, solvatesand polymorphs of these compositions, as well as other small moleculesthat may target a protein of interest. These binding moieties are linkedto the ubiquitin ligase binding moiety preferably through a linker inorder to present a target protein (to which the protein target moiety isbound) in proximity to the ubiquitin ligase for ubiquitination anddegradation.

Any protein, which can bind to a protein target moiety or PTM group andacted on or degraded by a ubiquitin ligase is a target protein accordingto the present disclosure. In general, target proteins may include, forexample, structural proteins, receptors, enzymes, cell surface proteins,proteins pertinent to the integrated function of a cell, includingproteins involved in catalytic activity, aromatase activity, motoractivity, helicase activity, metabolic processes (anabolism andcatabolism), antioxidant activity, proteolysis, biosynthesis, proteinswith kinase activity, oxidoreductase activity, transferase activity,hydrolase activity, lyase activity, isomerase activity, ligase activity,enzyme regulator activity, signal transducer activity, structuralmolecule activity, binding activity (protein, lipid carbohydrate),receptor activity, cell motility, membrane fusion, cell communication,regulation of biological processes, development, cell differentiation,response to stimulus, behavioral proteins, cell adhesion proteins,proteins involved in cell death, proteins involved in transport(including protein transporter activity, nuclear transport, iontransporter activity, channel transporter activity, carrier activity,permease activity, secretion activity, electron transporter activity,pathogenesis, chaperone regulator activity, nucleic acid bindingactivity, transcription regulator activity, extracellular organizationand biogenesis activity, translation regulator activity. Proteins ofinterest can include proteins from eukaryotes and prokaryotes includinghumans as targets for drug therapy, other animals, includingdomesticated animals, microbials for the determination of targets forantibiotics and other antimicrobials and plants, and even viruses, amongnumerous others.

In still other embodiments, the PTM group is a haloalkyl group, whereinsaid alkyl group generally ranges in size from about 1 or 2 carbons toabout 12 carbons in length, often about 2 to 10 carbons in length, oftenabout 3 carbons to about 8 carbons in length, more often about 4 carbonsto about 6 carbons in length. The haloalkyl groups are generally linearalkyl groups (although branched-chain alkyl groups may also be used) andare end-capped with at least one halogen group, preferably a singlehalogen group, often a single chloride group. Haloalkyl PT, groups foruse in the present disclosure are preferably represented by the chemicalstructure —(CH₂)_(v)-Halo where v is any integer from 2 to about 12,often about 3 to about 8, more often about 4 to about 6. Halo may be anyhalogen, but is preferably C1 or Br, more often C1.

In another embodiment, the present disclosure provides a library ofcompounds. The library comprises more than one compound wherein eachcomposition has a formula of A-B, wherein A is a ubiquitin pathwayprotein binding moiety (preferably, an E3 ubiquitin ligase moiety asotherwise disclosed herein) and B is a protein binding member of amolecular library, wherein A is coupled (preferably, through a linkermoiety) to B, and wherein the ubiquitin pathway protein binding moietyrecognizes an ubiquitin pathway protein, in particular, an E3 ubiquitinligase, such as cereblon. In a particular embodiment, the librarycontains a specific cereblon E3 ubiquitin ligase binding moiety bound torandom target protein binding elements (e.g., a chemical compoundlibrary). As such, the target protein is not determined in advance andthe method can be used to determine the activity of a putative proteinbinding element and its pharmacological value as a target upondegradation by ubiquitin ligase.

The present disclosure may be used to treat a number of disease statesand/or conditions, including any disease state and/or condition in whichproteins are dysregulated and where a patient would benefit from thedegradation of proteins.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,additive or excipient, and optionally an additional bioactive agent. Thetherapeutic compositions modulate protein degradation in a patient orsubject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., cancer (such as prostate cancer) andKennedy's Disease. In certain additional embodiments, the disease isprostate cancer.

In alternative aspects, the present disclosure relates to a method fortreating a disease state or ameliorating the symptoms of a disease orcondition in a subject in need thereof by degrading a protein orpolypeptide through which a disease state or condition is modulatedcomprising administering to said patient or subject an effective amount,e.g., a therapeutically effective amount, of at least one compound asdescribed hereinabove, optionally in combination with a pharmaceuticallyacceptable carrier, additive or excipient, and optionally an additionalbioactive agent, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.The method according to the present disclosure may be used to treat alarge number of disease states or conditions including cancer, by virtueof the administration of effective amounts of at least one compounddescribed herein. The disease state or condition may be a disease causedby a microbial agent or other exogenous agent such as a virus, bacteria,fungus, protozoa or other microbe or may be a disease state, which iscaused by overexpression of a protein, which leads to a disease stateand/or condition.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The term “target protein” is used to describe a protein or polypeptide,which is a target for binding to a compound according to the presentdisclosure and degradation by ubiquitin ligase hereunder. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. These binding moieties are linked to CLM or ULM groupsthrough linker groups L.

Target proteins which may be bound to the protein target moiety anddegraded by the ligase to which the ubiquitin ligase binding moiety isbound include any protein or peptide, including fragments thereof,analogues thereof, and/or homologues thereof. Target proteins includeproteins and peptides having any biological function or activityincluding structural, regulatory, hormonal, enzymatic, genetic,immunological, contractile, storage, transportation, and signaltransduction. In certain embodiments, the target proteins includestructural proteins, receptors, enzymes, cell surface proteins, proteinspertinent to the integrated function of a cell, including proteinsinvolved in catalytic activity, aromatase activity, motor activity,helicase activity, metabolic processes (anabolism and catabolism),antioxidant activity, proteolysis, biosynthesis, proteins with kinaseactivity, oxidoreductase activity, transferase activity, hydrolaseactivity, lyase activity, isomerase activity, ligase activity, enzymeregulator activity, signal transducer activity, structural moleculeactivity, binding activity (protein, lipid carbohydrate), receptoractivity, cell motility, membrane fusion, cell communication, regulationof biological processes, development, cell differentiation, response tostimulus, behavioral proteins, cell adhesion proteins, proteins involvedin cell death, proteins involved in transport (including proteintransporter activity, nuclear transport, ion transporter activity,channel transporter activity, carrier activity, permease activity,secretion activity, electron transporter activity, pathogenesis,chaperone regulator activity, nucleic acid binding activity,transcription regulator activity, extracellular organization andbiogenesis activity, translation regulator activity. Proteins ofinterest can include proteins from eukaryotes and prokaryotes, includingmicrobes, viruses, fungi and parasites, including humans, microbes,viruses, fungi and parasites, among numerous others, as targets for drugtherapy, other animals, including domesticated animals, microbials forthe determination of targets for antibiotics and other antimicrobialsand plants, and even viruses, among numerous others.

More specifically, a number of drug targets for human therapeuticsrepresent protein targets to which protein target moiety may be boundand incorporated into compounds according to the present disclosure.These include proteins which may be used to restore function in numerouspolygenic diseases, including for example B7.1 and B7, TINFR1m, TNFR2,NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5areceptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IVphosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclaseinhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1,cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e.,Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease,thymidylate synthase, purine nucleoside phosphorylase, GAPDHtrypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokinereceptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase,influenza, neuramimidase, hepatitis B reverse transcriptase, sodiumchannel, multi drug resistance (MDR), protein P-glycoprotein (and MRP),tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4integrin, selectins, CD40/CD40L, newokinins and receptors, inosinemonophosphate dehydrogenase, p38 MAP Kinase, Ras1Raf1MEWERK pathway,interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNAhelicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3Cprotease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus(CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases,vascular endothelial growth factor, oxytocin receptor, microsomaltransfer protein inhibitor, bile acid transport inhibitor, 5 alphareductase inhibitors, angiotensin 11, glycine receptor, noradrenalinereuptake receptor, endothelin receptors, neuropeptide Y and receptor,estrogen receptors, androgen receptors (AR), adenosine receptors,adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2,P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyl transferase,TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR,vitronectin receptor, integrin receptor, Her-21 neu, telomeraseinhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase.Additional protein targets include, for example, ecdysone20-monooxygenase, ion channel of the GABA gated chloride channel,acetylcholinesterase, voltage-sensitive sodium channel protein, calciumrelease channel, and chloride channels. Still further target proteinsinclude Acetyl-CoA carboxylase, adenylosuccinate synthetase,protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

Haloalkane dehalogenase enzymes are another target of specific compoundsaccording to the present disclosure. Compounds according to the presentdisclosure which contain chloroalkane peptide binding moieties (C₁-C₁₂often about C₂-C₁₀ alkyl halo groups) may be used to inhibit and/ordegrade haloalkane dehalogenase enzymes which are used in fusionproteins or related diagnostic proteins as described inPCT/US2012/063401 filed Dec. 6, 2011 and published as WO 2012/078559 onJun. 14, 2012, the contents of which is incorporated by referenceherein.

These various protein targets may be used in screens that identifycompound moieties which bind to the protein and by incorporation of themoiety into compounds according to the present disclosure, the level ofactivity of the protein may be altered for therapeutic end result.

The term “protein target moiety” or PTM is used to describe a smallmolecule which binds to a target protein or other protein or polypeptideof interest and places/presents that protein or polypeptide in proximityto an ubiquitin ligase such that degradation of the protein orpolypeptide by ubiquitin ligase may occur. Non-limiting examples ofsmall molecule target protein binding moieties include Hsp90 inhibitors,kinase inhibitors, MDM2 inhibitors, compounds targeting Human BETBromodomain-containing proteins, HDAC inhibitors, human lysinemethyltransferase inhibitors, angiogenesis inhibitors, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR),among numerous others. The compositions described below exemplify someof the members of these nine types of small molecule target protein.

Exemplary protein target moieties according to the present disclosureinclude, haloalkane halogenase inhibitors, Hsp90 inhibitors, kinaseinhibitors, MDM2 inhibitors, compounds targeting Human BETBromodomain-containing proteins, HDAC inhibitors, human lysinemethyltransferase inhibitors, angiogenesis inhibitors, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

The compositions described below exemplify some of the members of thesetypes of small molecule target protein binding moieties. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. References which are cited hereinbelow are incorporated byreference herein in their entirety.

I. Heat Shock Protein 90 (HSP90) Inhibitors:

HSP90 inhibitors as used herein include, but are not limited to:

1. The HSP90 inhibitors identified in Vallee, et al., “Tricyclic Seriesof Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery ofTricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90Molecular Chaperone (2011) J. Med. Chem. 54: 7206, including YKB(N-[4-(3H-imidazo[4,5-C]Pyridin-2-yl)-9H-Fluoren-9-yl]-succinamide):

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the terminal amide group;

2. The HSP90 inhibitor p54 (modified)(8-[(2,4-dimethylphenyl)sulfanyl]-3]pent-4-yn-1-yl-3H-purin-6-amine):

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the terminal acetylene group;

3. The HSP90 inhibitors (modified) identified in Brough, et al.,“4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential TherapeuticAgents for the Treatment of Cancer”, J. MED. CHEM. vol: 51, pag: 196(2008), including the compound 2GJ(5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide)having the structure:

derivatized, where a linker group L or a -(L-CLM) group is attached, forexample, via the amide group (at the amine or at the alkyl group on theamine);

4. The HSP90 inhibitors (modified) identified in Wright, et al.,Structure-Activity Relationships in Purine-Based Inhibitor Binding toHSP90 Isoforms, Chem Biol. 2004 June; 11(6):775-85, including the HSP90inhibitor PU3 having the structure:

derivatized where a linker group L or -(L-CLM) is attached, for example,via the butyl group; and

5. The HSP90 inhibitor geldanamycin((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1](derivatized) or any of its derivatives (e.g.17-alkylamino-17-desmethoxygeldanamycin (“17-AAG”) or17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin (“17-DMAG”))(derivatized, where a linker group L or a -(L-CLM) group is attached,for example, via the amide group).

II. Kinase and Phosphatase Inhibitors:

Kinase inhibitors as used herein include, but are not limited to:

1. Erlotinib Derivative Tyrosine Kinase Inhibitor:

where R is a linker group L or a -(L-CLM) group attached, for example,via the ether group;

2. The kinase inhibitor sunitinib (derivatized):

derivatized where R is a linker group L or a -(L-CLM) group attached,for example, to the pyrrole moiety;

3. Kinase Inhibitor sorafenib (derivatized):

derivatized where R is a linker group L or a -(L-CLM) group attached,for example, to the amide moiety;

4. The kinase inhibitor desatinib (derivatized):

derivatized where R is a linker group L or a -(L-CLM) attached, forexample, to the pyrimidine;

5. The kinase inhibitor lapatinib (derivatized):

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the terminal methyl of the sulfonyl methyl group;

6. The kinase inhibitor U09-CX-5279 (derivatized):

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the amine (aniline), carboxylic acid or amine alpha tocyclopropyl group, or cyclopropyl group;

7. The kinase inhibitors identified in Millan, et al., Design andSynthesis of Inhaled P38 Inhibitors for the Treatment of ChronicObstructive Pulmonary Disease, J. MED. CHEM. vol: 54, pag: 7797 (2011),including the kinase inhibitors Y1W and Y1× (Derivatized) having thestructures:

YIX(1-ethyl-3-((2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea,derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the ^(i)propyl group;

1-(3-ten-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)ureaderivatized where a linker group L or a -(L-CLM) group is attached, forexample, preferably via either the i-propyl group or the t-butyl group;

8. The kinase inhibitors identified in Schenkel, et al., Discovery ofPotent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors J.Med. Chem., 2011, 54 (24), pp 8440-8450, including the compounds 6TP andOTP (Derivatized) having the structures:

4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamideThienopyridine 19 derivatized where a linker group L or a -(L-CLM) groupis attached, for example, via the terminal methyl group bound to amidemoiety;

4-amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamideThienopyridine 8 derivatized where a linker group L or a -(L-CLM) groupis attached, for example, via the terminal methyl group bound to theamide moiety;

9. The kinase inhibitors identified in Van Eis, et al.,“2,6-Naphthyridines as potent and selective inhibitors of the novelprotein kinase C isozymes”, Biorg. Med. Chem. Lett. 2011 Dec. 15;21(24):7367-72, including the kinase inhibitor 07U having the structure:

2-methyl-N˜1˜-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diaminederivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the secondary amine or terminal amino group;

10. The kinase inhibitors identified in Lountos, et al., “StructuralCharacterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2),a Drug Target for Cancer Therapy”, J. STRUCT. BIOL. vol: 176, pag: 292(2011), including the kinase inhibitor YCF having the structure:

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via either of the terminal hydroxyl groups;

11. The kinase inhibitors identified in Lountos, et al., “StructuralCharacterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2),a Drug Target for Cancer Therapy”, J. STRUCT. BIOL. vol: 176, pag: 292(2011), including the kinase inhibitors XK9 and NXP (derivatized) havingthe structures:

N-{4-[(1E)-N—(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide;

N-{4-[(1E)-N-CARBAMIMIDOYLETHANEHYDRAZONOYL]PHENYL}-1H-INDOLE-3-CARBOXAMIDEderivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the terminal hydroxyl group (XK9) or the hydrazone group(NXP);

12. The kinase inhibitor afatinib (derivatized)(N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide)(Derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the aliphatic amine group);

13. The kinase inhibitor fostamatinib (derivatized)([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyldisodium phosphate hexahydrate) (Derivatized where a linker group L or a-(L-CLM) group is attached, for example, via a methoxy group);

14. The kinase inhibitor gefitinib (derivatized)(N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine):

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via a methoxy or ether group;

15. The kinase inhibitor lenvatinib (derivatized)(4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide)(derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the cyclopropyl group);

16. The kinase inhibitor vandetanib (derivatized)(N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine)(derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the methoxy or hydroxyl group);

17. The kinase inhibitor vemurafenib (derivatized) (propane-1-sulfonicacid{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide),derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the sulfonyl propyl group;

18. The kinase inhibitor Gleevec (derivatized):

derivatized where R as a linker group L or a -(L-CLM) group is attached,for example, via the amide group or via the aniline amine group;

19. The kinase inhibitor pazopanib (derivatized) (VEGFR3 inhibitor):

derivatized where R is a linker group L or a -(L-CLM) group attached,for example, to the phenyl moiety or via the aniline amine group;

20. The kinase inhibitor AT-9283 (Derivatized) Aurora Kinase Inhibitor

where R is a linker group L or a -(L-CLM) group attached, for example,to the phenyl moiety);

21. The kinase inhibitor TAE684 (derivatized) ALK inhibitor

where R is a linker group L or a -(L-CLM) group attached, for example,to the phenyl moiety);

22. The kinase inhibitor nilotanib (derivatized) Abl inhibitor:

derivatized where R is a linker group L or a -(L-CLM) group attached,for example, to the phenyl moiety or the aniline amine group;

23. Kinase Inhibitor NVP-BSK805 (derivatized) JAK2 Inhibitor

derivatized where R is a linker group L or a -(L-CLM) group attached,for example, to the phenyl moiety or the diazole group;

24. Kinase Inhibitor crizotinib Derivatized Alk Inhibitor

derivatized where R is a linker group L or a -(L-CLM) group attached,for example, to the phenyl moiety or the diazole group;

25. Kinase Inhibitor JNJ FMS (derivatized) Inhibitor

derivatized where R is a linker group L or a -(L-CLM) group attached,for example, to the phenyl moiety;

26. The kinase inhibitor foretinib (derivatized) Met Inhibitor

derivatized where R is a linker group L or a -(L-CLM) group attached,for example, to the phenyl moiety or a hydroxyl or ether group on thequinoline moiety;

27. The allosteric Protein Tyrosine Phosphatase Inhibitor PTP1B(derivatized):

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at R, as indicated;

28. The inhibitor of SHP-2 Domain of Tyrosine Phosphatase (derivatized):

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at R;

29. The inhibitor (derivatized) of BRaf (BRaf^(v600E))/MEK:

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at R;

30. Inhibitor (derivatized) of Tyrosine Kinase ABL

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at R;

31. The kinase inhibitor OSI-027 (derivatized) mTORC1/2 inhibitor

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at R;

32. The kinase inhibitor OSI-930 (derivatized) c-Kit/KDR inhibitor

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at R; and

33. The kinase inhibitor OSI-906 (derivatized) IGF1R/IR inhibitor

derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at R.

Wherein, in any of the embodiments described in sections I-XVII, “R”designates a site for attachment of a linker group L or a -(L-CLM) groupon the piperazine moiety.

III. HDM2/1VIDM2 Inhibitors:

HDM2/MDM2 inhibitors as used herein include, but are not limited to:

1. The HDM2/MDM2 inhibitors identified in Vassilev, et al., In vivoactivation of the p53 pathway by small-molecule antagonists of MDM2,SCIENCE vol: 303, pag: 844-848 (2004), and Schneekloth, et al., Targetedintracellular protein degradation induced by a small molecule: En routeto chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908,including (or additionally) the compounds nutlin-3, nutlin-2, andnutlin-1 (derivatized) as described below, as well as all derivativesand analogs thereof:

(derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at the methoxy group or as a hydroxyl group);

(derivatized where a linker group L or a -(L-CLM) group is attached, forexample, at the methoxy group or hydroxyl group);

(derivatized where a linker group L or a -(L-CLM) group is attached, forexample, via the methoxy group or as a hydroxyl group); and

2. Trans-4-Iodo-4′-Boranyl-Chalcone

(derivatized where a linker group L or a linker group L or a -(L-CLM)group is attached, for example, via a hydroxy group).

IV. Compounds Targeting Human BET Bromodomain-Containing Proteins:

In certain embodiments, “PTM” can be ligands binding to Bromo- andExtra-terminal (BET) proteins BRD2, BRD3 and BRD4. Compounds targetingHuman BET Bromodomain-containing proteins include, but are not limitedto the compounds associated with the targets as described below, where“R” or “linker” designates a site for linker group L or a -(L-CLM) groupattachment, for example:

1. JQ1, Filippakopoulos et al. Selective inhibition of BET bromodomains.Nature (2010):

2. I-BET, Nicodeme et al. Suppression of Inflammation by a SyntheticHistone Mimic. Nature (2010). Chung et al. Discovery andCharacterization of Small Molecule Inhibitors of the BET FamilyBromodomains. J. Med Chem. (2011):

3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act asAcetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770.

4. I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin asan Effective Treatment for MLL-fusion Leukemia. Nature (2011):

5. Carbazole type (US 2015/0256700)

6. Pyrrolopyridone type (US 2015/0148342)

7. Tetrahydroquinoline type (WO 2015/074064)

8. Triazolopyrazine type (WO 2015/067770)

9. Pyridone type (WO 2015/022332)

10. Quinazolinone type (WO 2015/015318)

11. Dihydropyridopyrazinone type (WO 2015/011084)

(Where R or L or linker, in each instance, designates a site forattachment, for example, of a linker group L or a -(L-CLM) group).

In any aspect or embodiment described herein, the claimed structure thePTM may be composed of tricyclic diazepine or tricyclic azepine as aBET/BRD4 targeting moiety (PTM-a), where the dashed lines indicate thelinker connection trajectory and three sites are defined to whichlinkers may be attached:

wherein:

-   -   A and B are independently an aromatic ring, a heteroaromatic        ring, a 5-membered carbocyclic, a 6-membered carbocyclic, a        5-membered heterocyclic, a 6-membered heterocyclic, a thiophene,        a pyrrole, a pyrazole, a pyridine, a pyrimidine, a pyrazine,        optionally substituted by alkyl, alkoxy, halogen, nitrile or        another aromatic or heteroaromatic ring, where A is fused to the        central azepine (Y1=C) or diazepine (Y1=N) moiety;    -   Y1, Y2, and Y3 and Y4 can be carbon, nitrogen or oxygen for to        form a fused 5-membered aromatic ring as triazole or isoxazole;        and    -   Z1 is methyl, or lower alkyl group.

The fragment of PTM-a as BET/BRD4 targeting moiety is described in theliterature (WO 2016/069578; WO2014/001356; WO2016/050821; WO2015/195863; WO 2014/128111).

In any aspect or embodiment described herein comprising the structureCLM-L-PTM-a, PTM-a can be represented by the following generalstructures, where dashed line indicates a possible linker connectionpoint. In structure PTM-aa through PTM-ai, the substitution pattern of Xand Y can be mono- or bis-substitution.

In any aspect or embodiment described herein, the structures of PTM-a asthe BET/BRD4 targeting moiety includes, wherein the dashed lineindicates the connection point between the BET/BRD4 targeting moiety andthe linkers:

V. HDAC Inhibitors:

HDAC Inhibitors (derivatized) include, but are not limited to:

1. Finnin, M. S. et al. Structures of Histone Deacetylase HomologueBound to the TSA and SAHA Inhibitors. Nature 40, 188-193 (1999).

(Derivatized where “R” designates a site for attachment, for example, ofa linker group L or a -(L-CLM) group); and

2. Compounds as defined by formula (I) of PCT WO0222577 (“DEACETYLASEINHIBITORS”) (Derivatized where a linker group L or a -(L-CLM) group isattached, for example, via the hydroxyl group);

VI. Human Lysine Methyltransferase Inhibitors:

Human Lysine Methyltransferase inhibitors include, but are not limitedto:

1. Chang et al. Structural Basis for G9a-Like protein LysineMethyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009)16(3) 312.

(Derivatized where “R” designates a site for attachment, for example, ofa linker group L or a -(L-CLM) group);

2. Liu, F. et al Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline asa Potent and Selective Inhibitor of Histone Methyltransferase G9a. J.Med. Chem. (2009) 52(24) 7950.

(Derivatized where “R” designates a potential site for attachment, forexample, of a linker group L or a -(L-CLM) group);

3. Azacitidine (derivatized)(4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (Derivatized wherea linker group L or a -(L-CLM) group is attached, for example, via thehydroxy or amino groups); and

4. Decitabine (derivatized)(4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-1, 3,5-triazin-2(1H)-one) (Derivatized where a linker group L or a -(L-CLM)group is attached, for example, via either of the hydroxy groups or atthe amino group).

VII. Angiogenesis Inhibitors:

Angiogenesis inhibitors include, but are not limited to:

1. GA-1 (derivatized) and derivatives and analogs thereof, having thestructure(s) and binding to linkers as described in Sakamoto, et al.,Development of Protacs to target cancer-promoting proteins forubiquitination and degradation, Mol Cell Proteomics 2003 December;2(12):1350-8;

2. Estradiol (derivatized), which may be bound to a linker group L or a-(L-CLM) group as is generally described in Rodriguez-Gonzalez, et al.,Targeting steroid hormone receptors for ubiquitination and degradationin breast and prostate cancer, Oncogene (2008) 27, 7201-7211;

3. Estradiol, testosterone (derivatized) and related derivatives,including but not limited to DHT and derivatives and analogs thereof,having the structure(s) and binding to a linker group L or a -(L-CLM)group as generally described in Sakamoto, et al., Development of Protacsto target cancer-promoting proteins for ubiquitination and degradation,Mol Cell Proteomics 2003 December; 2(12):1350-8; and

4. Ovalicin, fumagillin (derivatized), and derivatives and analogsthereof, having the structure(s) and binding to a linker group L or a-(L-CLM) group as is generally described in Sakamoto, et al., Protacs:chimeric molecules that target proteins to the Skp1-Cullin-F box complexfor ubiquitination and degradation Proc Natl Acad Sci USA. 2001 Jul. 17;98(15):8554-9 and U.S. Pat. No. 7,208,157.

VIII. Immunosuppressive Compounds:

Immunosuppressive compounds include, but are not limited to:

1. AP21998 (derivatized), having the structure(s) and binding to alinker group L or a -(L-CLM) group as is generally described inSchneekloth, et al., Chemical Genetic Control of Protein Levels:Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004, 126,3748-3754;

2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, andmethylprednisolone) (Derivatized where a linker group L or a -(L-CLM)group is to bound, e.g. to any of the hydroxyls) and beclometasonedipropionate (Derivatized where a linker group or a -(L-CLM) is bound,e.g. to a proprionate);

3. Methotrexate (Derivatized where a linker group or a -(L-CLM) groupcan be bound, e.g. to either of the terminal hydroxyls);

4. Ciclosporin (Derivatized where a linker group or a -(L-CLM) group canbe bound, e.g. at any of the butyl groups);

5. Tacrolimus (FK-506) and rapamycin (Derivatized where a linker group Lor a -(L-CLM) group can be bound, e.g. at one of the methoxy groups);and

6. Actinomycins (Derivatized where a linker group L or a -(L-CLM) groupcan be bound, e.g. at one of the isopropyl groups).

IX. Compounds Targeting the Aryl Hydrocarbon Receptor (AHR):

Compounds targeting the aryl hydrocarbon receptor (AHR) include, but arenot limited to:

1. Apigenin (Derivatized in a way which binds to a linker group L or a-(L-CLM) group as is generally illustrated in Lee, et al., TargetedDegradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: AUseful Chemical Genetic Tool, Chem Bio Chem Volume 8, Issue 17, pages2058-2062, Nov. 23, 2007); and

2. SR1 and LGC006 (derivatized such that a linker group L or a -(L-CLM)is bound), as described in Boitano, et al., Aryl Hydrocarbon ReceptorAntagonists Promote the Expansion of Human Hematopoietic Stem Cells,Science 10 Sep. 2010: Vol. 329 no. 5997 pp. 1345-1348.

X. Compounds Targeting RAF Receptor (Kinase):

PLX4032

(Derivatized where “R” designates a site for linker group L or -(L-CLM)group attachment, for example).

Any protein, which can bind to a protein target moiety or PTM group andacted on or degraded by an ubiquitin ligase (e.g., RAF) is a targetprotein according to the present disclosure.

In any aspect or embodiment described herein, the PTM targets and/orbinds RAF (i.e., a Raf or BRaf targeting moiety). For example, in anyaspect or embodiment described herein, the PTM may comprise a chemicalgroup selected from the group of chemical structures consisting ofPTM-Ia or PTM-Ib:

wherein:

-   -   double dotted bonds are aromatic bonds;    -   V_(PTM), W_(PTM), X_(PTM), Y_(PTM), Z_(PTM) is one of the        following combinations: C, CH, N, N, C; C, N,

N, CH, C; C, O, C, CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S,C; C, CH, N, CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N,CH, C, N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N,N, C;

-   -   X_(PTM35), X_(PTM36), X_(PTM37), and X_(PTM38) are independently        selected from CH and N;    -   R_(PTM1) is covalently joined to a ULM, a chemical linker group        (L), a CLM, an ILM, a VLM,

MLM, a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof;

-   -   R_(PTM2) is hydrogen, halogen, aryl, methyl, ethyl, OCH₃, NHCH₃        or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM3) is absent, hydrogen, aryl, methyl, ethyl, other alkyl,        cyclic alkyl, OCH₃, NHCH₃ or Ml-CH₂—CH₂-M2, wherein M1 is CH₂, O        and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or        heterocycle;    -   R_(PTM4) is hydrogen, halogen, aryl, methyl, ethyl, OCH₃, NHCH₃        or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; and    -   R_(PTM5) is selected from the group consisting of

In any aspect or embodiment described herein, the PTM may comprise achemical group selected from the group of chemical structures consistingof PTM-IIa or PTM-IIb:

-   -   X_(PTM1), X_(PTM2), X_(PTM3), X_(PTM4), X_(PTM5), and X_(PTM6)        are independently selected from CH or N;    -   R_(PTM5a) is selected from the group consisting of: bond,        optionally substituted amine, optionally substituted amide        (e.g., optionally substituted with an alkyl, methyl, ethyl,

propyl, or butyl group), H,

-   -    —NHC(O)R_(PTM5);    -   R_(PTM5) is selected from the group consisting of

R_(PTM6a) and R_(PTM6b) are each independently selected from hydrogen,halogen, or optionally substituted C₁-C₆ alkyl (linear, branched,optionally substituted);

-   -   R_(PTM6) is absent, hydrogen, halogen, aryl, methyl, ethyl,        OCH₃, NHCH₃ or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and        M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM7) is absent, hydrogen, halogen, aryl, methyl, ethyl,        OCH₃, NHCH₃ or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O or NH, and M2        is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM8), R_(PTM9) or R_(PTM10) are independently selected from        the group consisting of absent, hydrogen, halogen, aryl,        heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH₃,        NHCH₃ or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM11) is absent, hydrogen, halogen, methyl, ethyl, OCH₃, NH        CH₃ or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O or NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;

and at least one of R_(PTM8), R_(PTM9) or R_(PTM10) is modified to becovalently joined to a ULM, a chemical linker group (L), a CLM, an ILM,a VLM, MLM, a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combinationthereof.

In certain embodiments, the PTM may comprise a chemical group selectedfrom the group of chemical structures consisting of:

wherein R_(PTM5), R_(PTM6a), R_(PTM6b), R_(PTM6), R_(PTM7), R_(PTM8),R_(PTM9), R_(PTM10), R_(PTM11) are as described herein.

In some embodiments, when R_(PTM9) is the covalently joined position,R_(PTM7) and R_(PTM8) can be connected together via a covalent bond in away to form a bicyclic group with the ring to which R_(PTM7) andR_(PTM8) are attached.

In other embodiments, when R_(PTM8) is the covalently joined position,R_(PTM9) and R_(PTM10) can be connected together via a covalent bond ina way to form a bicyclic group with the ring to which R_(PTM9) andR_(PTM10) are attached.

In further embodiments, when R_(PTM10) is the covalently joinedposition, R_(PTM8) and R_(PTM9) can be connected together via a covalentbond in a way to form a bicyclic group with the ring to which R_(PTM8)and R_(PTM9) are attached.

In any aspect or embodiment described herein, the PTM may comprise achemical group selected from the group of chemical structures consistingof PTM-III:

wherein:

-   -   X_(PTM7), X_(PTM8), X_(PTM9), X_(PTM10), X_(PTM11), X_(PTM12),        X_(PTM13), X_(PTM14), X_(PTM15), X_(PTM16), X_(PTM17),        X_(PTM18), X_(PTM19), X_(PTM20) are independently CH or N;    -   R_(PTM12), R_(PTM13), R_(PTM14), R_(PTM15), R_(PTM16),        R_(PTM17), R_(PTM18), R_(PTM19) are independently selected from        the group consisting of absent, hydrogen, halogen, aryl,        heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl,        OCH₃, NHCH₃ or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and        M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM20) is a small group containing less than four        non-hydrogen atoms;    -   R_(PTM21) is selected from the group consisting of        trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl,        isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, OCH₃, NHCH₃, dimethylamino        or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O or NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; and at least        one of R_(PTM12), R_(PTM13) and R_(PTM16) is modified to be        covalently joined to a ULM, a chemical linker group (L), a CLM,        an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or        combination thereof.

In some embodiments, when R_(PTM12) is the covalently joined position,R_(PTM13) and R_(PTM14) can be connected together via a covalent bond ina way to form a bicyclic group with the ring to which R_(PTM13) andR_(PTM14) are attached; and/or R_(PTM15) and R_(PTM16) can be connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM15) and R_(PTM16) are attached.

In other embodiments, when R_(PTM13) is the covalently joined position,R_(PTM12) and R_(PTM16) can be connected together via a covalent bond ina way to form a bicyclic group with the ring to which R_(PTM12) andR_(PTM16) are attached; and/or R_(PTM15) and R_(PTM16) can be connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM15) and R_(PTM16) are attached.

In further embodiments, when R_(PTM16) is the covalently joinedposition, R_(PTM12) and R_(PTM13) can be connected together via acovalent bond in a way to form a bicyclic group with the ring to whichR_(PTM12) and R_(PTM13) are attached; and/or R_(PTM13) and R_(PTM14) canbe connected together via a covalent bond in a way to form a bicyclicgroup with the ring to which R_(PTM13) and R_(PTM14) are attached.

In any aspect or embodiment described herein, the PTM may comprise achemical group selected from the group of chemical structures consistingof PTM-IVa or PTM-IVb:

wherein:

-   -   X_(PTM21), X_(PTM22), X_(PTM23), X_(PTM24), X_(PTM25),        X_(PTM26), X_(PTM27), X_(PTM28), X_(PTM29), X_(PTM30),        X_(PTM31), X_(PTM32), X_(PTM33), X_(PTM34) are independently CH        or N;    -   R_(PTM22) is selected from the group consisting of

-   -   R_(PTM25a) and R_(PTM25b) are each independently selected from        hydrogen, halogen, or C₁-C₆ alkyl (linear, branched, optionally        substituted);    -   R_(PTM23), R_(PTM24), R_(PTM28), R_(PTM29), R_(PTM30),        R_(PTM31), R_(PTM32) are independently selected from the group        consisting of absent, bond, hydrogen, halogen, aryl (optionally        substituted), heteroaryl (optionally substituted), cycloalkyl        (optionally substituted), heterocycle (optionally substituted),        methyl, ethyl (optionally substituted), other alkyl (linear,        branched, optionally substituted), OCH₃, NHCH₃ or M1-CH₂—CH₂-M2,        wherein M1 is CH₂, O and NH, and M2 is hydrogen, alkyl (linear,        branched, optionally substituted), cyclic alkyl (optionally        substituted), aryl (optionally substituted) or heterocycle        (optionally substituted); and    -   R_(PTM25) is absent, hydrogen, halogen, C₁-C₆ alkyl (linear,        branched, optionally substituted),

OCH₃, NHCH₃ or SCH₃;

-   -   R_(PTM26) is absent, hydrogen, halogen, C₁-C₆ alkyl (linear,        branched, optionally substituted), OCH₃, NHCH₃ or SCH₃;    -   R_(PTM27) is selected from the group consisting of absent,        hydrogen, halogen, C₁-C₆ alkyl (linear, branched, optionally        substituted), OCH₃, NHCH₃ or SCH₃; and    -   at least one of R_(PTM24), R_(PTM29), R_(PTM32) is modified to        be covalently joined to a ULM, a chemical linker group (L), a        CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a VLM′, a MLM′,        or combination thereof.

In some embodiments, when R_(PTM24) is the covalently joined position,R_(PTM31) and R_(PTM32) can be connected together via a covalent bond ina way to form a bicyclic group with the ring to which R_(PTM31) andR_(PTM32) are attached; or R_(PTM29) and R_(PTM30) can be connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM29) and R_(PTM30) are attached.

In other embodiments, when R_(PTM29) is the covalently joined position,R_(PTM24) and R_(PTM32) can be connected together via a covalent bond ina way to form a bicyclic group with the ring to which R_(PTM24) andR_(PTM32) are attached; and/or R_(PTM31) and R_(PTM32) can be connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM31) and R_(PTM32) are attached.

In further embodiments, when R_(PTM32) is the covalently joinedposition, R_(PTM24) and R_(PTM29) can be connected together via acovalent bond in a way to form a bicyclic group with the ring to whichR_(PTM24) and R_(PTM29) are attached; and/or R_(PTM29) and R_(PTM30) canbe connected together via a covalent bond in a way to form a bicyclicgroup with the ring to which R_(PTM29) and R_(PTM30) are attached.

In any aspect or embodiments described herein, the PTM is selected fromthe group consisting of chemical structures PTM-1, PTM-2, PTM-3, PTM-4,PTM-5, PTM-6, PTM-7, and PTM-8:

XI. Compounds Targeting FKBP:

(Derivatized where “R” designates a site for a linker group L or a-(L-CLM) group attachment, for example).

XII. Compounds Targeting Androgen Receptor (AR)

1. RU59063 Ligand (derivatized) of Androgen Receptor

(Derivatized where “R” designates a site for a linker group L or a-(L-CLM) group attachment, for example).

2. SARM Ligand (derivatized) of Androgen Receptor

(Derivatized where “R” designates a site for a linker group L or a-(L-CLM) group attachment, for example).

3. Androgen Receptor Ligand DHT (derivatized)

(Derivatized where “R” designates a site for a linker group L or-(L-CLM) group attachment, for example).

4. MDV3100 Ligand (derivatized)

5. ARN-509 Ligand (derivatized)

6. Hexahydrobenzisoxazoles

7. Tetramethylcyclobutanes

8. In any aspect or embodiment described herein, the PTM is a chemicalmoiety that binds to the androgen receptor (AR). Various androgenreceptor binding compounds have been described in literature, includingvarious androgen derivatives such as testosterone, dihydrotestosterone,and metribolone (also known as methyltrienolone or R1881), andnon-steroidal compounds such as bicalutamide, enzalutamide, some ofwhich are described above. Those of ordinary skill in the art wouldappreciate that these androgen receptor binding compounds could bepotentially used as an androgen binding moiety (ABM) in a PROTACcompound. Such literature includes, but not limited to, G. F. Allan et.al, Nuclear Receptor Signaling, 2003, 1, e009; R. H. Bradbury et. al,Bioorganic & Medicinal Chemistry Letters, 2011 5442-5445; C. Guo et. al,Bioorganic & Medicinal Chemistry Letters, 2012 2572-2578; P. K.Poutiainen et. al, J. Med. Chem. 2012, 55, 6316-6327 A. Pepe et. al, J.Med. Chem. 2013, 56, 8280-8297; M. E. Jung et al, J. Med. Chem. 2010,53, 2779-2796, which are incorporated by reference herein

In any aspect or embodiment described herein, the ABM comprises astructure selected from, but not limited to the structures shown below,wherein a dashed line indicates the attachment point of a linker moietyor a ULM, such as a CLM:

wherein:

-   -   W¹ is aryl, heteroaryl, bicyclic, or biheterocyclic, each        independently substituted by 1 or more H, halo, hydroxyl, nitro,        CN, C≡CH, C₁₋₆ alkyl (linear, branched, optionally substituted;        for example, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionally        substituted; for example, optionally substituted by 1 or more        halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, or CF₃;    -   Y¹, Y² are each independently NR^(Y1), O, S;    -   Y³, Y⁴, Y⁵ are each independently a bond, O, NR^(Y2),        CR^(Y1)R^(Y2), C═O, C═S, SO, SO₂, heteroaryl, or aryl;    -   Q is a 3-6 membered ring with 0-4 heteroatoms, optionally        substituted with 0-6 R^(Q), each R^(Q), is independently H, C₁₋₆        alkyl (linear, branched, optionally substituted; for example,        optionally substituted by 1 or more halo, C₁₋₆ alkoxyl),        halogen, C₁₋₆ alkoxy, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 3-8 membered ring system        containing 0-2 heteroatoms);    -   R¹, R², R^(a), R^(b), R^(Y1), R^(Y2) are each independently H,        C₁₋₆ alkyl (linear, branched, optionally substituted; for        example, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), halogen, C₁₋₆ alkoxy, cyclic, heterocyclic, or R¹, R²        together with the atom they are attached to, form a 3-8 membered        ring system containing 0-2 heteroatoms);    -   W² is a bond, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, O, aryl, heteroaryl,        alicyclic, heterocyclic, biheterocyclic, biaryl, or        biheteroaryl, each optionally substituted by 1-10 R^(W2);    -   each R^(W2) is independently H, halo, C1-6 alkyl (linear,        branched, optionally substituted; for example, optionally        substituted by 1 or more F), —OR^(W2A), C₃₋₆ cycloalkyl, C₄₋₆        cycloheteroalkyl, C₁₋₆ alicyclic (optionally substituted),        heterocyclic (optionally substituted), aryl (optionally        substituted), or heteroaryl (optionally substituted), bicyclic        heteroaryl or aryl, OC₁₋₃ alkyl (optionally substituted), OH,        NH₂, NR^(Y1)R^(Y2), CN; and    -   R^(W2A) is H, C₁₋₆ alkyl (linear, branched), or C₁₋₆ heteroalkyl        (linear, branched), each optionally substituted by a cycloalkyl,        cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or        OC₁₋₃alkyl.

In any aspect or embodiment described herein, the W² is covalentlycoupled to one or more ULM or CLM groups, or a linker to which isattached one or more ULM or CLM groups as described herein.

In any aspect or embodiment described herein, W¹ is

wherein each R₂₂ is independently halo, H, optionally substituted alkyl,haloalkyl, cyano, or nitro; and each R₂₃ is independently H, halo, CF₃,optionally substituted alkyl, alkoxy, haloalkyl, cyano, or nitro.

In any aspect or embodiment described herein, W¹ is selected from thegroup consisting of:

In any aspect or embodiment described herein, the ABM comprises astructure selected from the following structures shown below, where a

indicates the attachment point of a linker or a ULM:

wherein:

-   -   R^(Q2) is a H, halogen, CH₃ or CF₃;    -   R^(Q3) is H, halo, hydroxyl, nitro, CN, C≡CH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionally        substituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, or        CF₃;    -   Y³, Y⁴, Y⁵ are each independently a bond, O, NR^(Y2),        CR^(Y1)R^(Y2), C═O, heteroaryl, or aryl,    -   R^(Y1), R^(Y2) are each independently H, or C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl, cyclic, or heterocyclic); and    -   R^(Q)each independently is H, C₁-C₆ alkyl (linear, branched,        optionally substituted by 1 or more halo, or C₁-6 alkoxyl), or        two R^(Q) together with the atom they are attached to, form a        3-8 membered ring system containing 0-2 heteroatoms.

In any aspect or embodiment described herein, each R^(Q) isindependently H or CH₃. In another embodiment R^(Q3) is CN.

In any aspect or embodiment described herein, the ABM comprises astructure selected from the following structures shown below, where a

indicates the attachment point of a linker or a ULM:

wherein:

-   -   R^(Q2) is a H, halogen, CN, CH₃ or CF₃; and    -   R^(Q3) is H, halo, hydroxyl, nitro, CN, C≡CH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionally        substituted by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, or        CF₃;    -   Y³, Y⁴, Y⁵ are each independently a bond, O, NR^(Y2),        CR^(Y1)R^(Y2), C═O, heteroaryl, or aryl; and    -   R^(Y1), R^(Y2) are each independently H or C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl, cyclic, or heterocyclic); and    -   X is N or C.

In any aspect or embodiment described herein, R^(Q3) is a CN.

In any aspect or embodiment described herein, the ABM comprises astructure shown below, where a dashed line indicates the attachmentpoint of a linker moiety or a ULM or a CLM:

wherein:

-   -   W¹ is

-   -   each R₂₂ is independently H or —CN;    -   each R₂₃ is independently H, halo, C₁-C₆ alkyl (linear,        branched, optionally substituted), C₁-C₆ alkoxy, or —CF₃;    -   Y³ is a bond or O;    -   Y⁴ is a bond or NH;    -   Y⁵ is a bond, C═O, C₁-C₆ heteroaryl, or C₁-C₆ aryl;    -   R¹, R², are each independently H, or C₁-C₆ alkyl (linear or        branched, optionally substituted; for example, optionally        substituted by 1 or more halo, or C₁₋₆ alkoxyl);    -   W² is a bond, C₁₋₆ aryl, C1-6 heteroaryl, C₁₋₆ alicyclic, or        C1-6 heterocyclic, biheterocyclic, biaryl, or biheteroaryl, each        optionally substituted by 1-10 R^(W2); and    -   each R^(W2) is independently H, or halo; and    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific.

In any aspect or embodiment described herein, the W² is covalentlycoupled to one or more ULM or CLM groups, or a linker to which isattached one or more ULM or CLM groups as described herein.

In any aspect or embodiment described herein, W¹ is selected from thegroup consisting of:

In any aspect or embodiment described herein, W² is selected from thegroup consisting of:

In any aspect or embodiment described herein, the ABM comprises astructure selected from, but not limited to the structures shown below,where a dashed line indicates the attachment point of a linker moiety ora ULM:

wherein:

-   -   W¹ is

-   -   each R₂₂ is independently H or —CN;    -   each R₂₃ is independently H, halo, or —CF₃;    -   Y¹, Y² are each independently O or S;    -   R¹, R², are each independently H or a methyl group;    -   W² is a bond, C₁₋₆ aryl, or heteroaryl, each optionally        substituted by 1, 2 or 3 R^(W2); and    -   each R^(W2) is independently H, halo, C₁₋₆ alkyl (optionally        substituted by 1 or more F), OC₁₋₃alkyl (optionally substituted        by 1 or more —F).

In any of the embodiments described herein, the W² is covalently coupledto one or more ULM or CLM groups, or a linker to which is attached oneor more ULM or CLM groups as described herein.

In certain additional embodiments, W¹ is selected from the groupconsisting of:

In any aspect or embodiment described herein, W₂ is selected from thegroup consisting of:

In any aspect or embodiment described herein, ABM is selected from thegroup consisting of:

In any aspect or embodiment described herein, the ABM comprises thestructure:

wherein:

-   -   W¹ is aryl, or heteroaryl, each independently substituted by 1        or more H, halo, hydroxyl, nitro, CN, C≡CH, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C1-6        alkoxyl), C1-6 alkoxyl (linear, branched, optionally substituted        by 1 or more halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, or CF₃;    -   Y³, Y⁴, Y⁵ are each independently a bond, O, NR^(Y2),        CR^(Y1)R^(Y2), C═O, C═S, SO, SO₂, heteroaryl, or aryl;    -   Q is a 4 membered alicyclic ring with 0-2 heteroatoms,        optionally substituted with 0-6 R^(Q), each R^(Q) is        independently H, C₁₋₆ alkyl (linear, branched, optionally        substituted by 1 or more halo, C₁₋₆ alkoxyl), or 2 R^(Q) groups        taken together with the atom they are attached to, form a 3-8        membered ring system containing 0-2 heteroatoms);    -   R^(Y1), R^(Y2) are each independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl);    -   W² is a bond, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, O, C₁₋₆ alicyclic,        heterocyclic, aryl, biheterocyclic, biaryl, or biheteroaryl, or        heteroaryl, each optionally substituted by 1, 2 or 3 R^(W2); and    -   each R^(W2) is independently H, halo, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more F), C1-6        heteroalkyl (linear, branched, optionally substituted),        —OR^(W2A)OC₁₋₃ alkyl (optionally substituted by 1 or more —F),        C₃₋₆ cycloalkyl, C₄₋₆ cycloheteroalkyl (optionally substituted),        C₁₋₆ alkyl (optionally substituted), C₁₋₆ alicyclic (optionally        substituted), heterocyclic (optionally substituted), aryl        (optionally substituted), heteroaryl (optionally substituted),        bicyclic heteroaryl (optionally substituted), bicyclic aryl, OH,        NH₂, NR^(Y1)R^(Y2), or CN; and    -   R^(W2A) is H, C₁₋₆ alkyl (linear, branched), or C1-6 heteroalkyl        (linear, branched), each optionally substituted by a cycloalkyl,        cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or        OC₁₋₃alkyl.

In any aspect or embodiment described herein, the description providesan androgen receptor binding compound comprising a structure of:

wherein:

-   -   W¹ is aryl, heteroaryl, bicyclic, or biheterocyclic, each        independently substituted by 1 or more H, halo, hydroxyl, nitro,        CN, C≡CH, C₁₋₆ alkyl (linear, branched, optionally substituted        by 1 or more halo, C₁₋₆ alkoxyl), C₁₋₆ alkoxyl (linear,        branched, optionally substituted by 1 or more halo), C₂₋₆        alkenyl, C₂₋₆ alkynyl, or CF₃; Y¹, Y² are each independently        NR^(Y1), O, or S;    -   Y³, Y⁴, Y⁵ are each independently a bond, O, NR^(Y2),        CR^(Y1)R^(Y2), C═O, C═S, SO, SO₂, heteroaryl, or aryl;    -   Q is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally substituted with 0-6 R^(Q), each R^(Q),        is independently H, C₁₋₆ alkyl (linear, branched, optionally        substituted by 1 or more halo, C₁₋₆ alkoxyl), or 2 R^(Q) groups        taken together with the atom they are attached to, form a 3-8        membered ring system containing 0-2 heteroatoms);    -   R¹, R², R^(a), R^(b), R^(Y1), R^(Y2) are each independently H,        C₁₋₆ alkyl (linear, branched, optionally substituted by 1 or        more halo, C₁₋₆ alkoxyl), or R¹, R² together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   W² is a bond, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, O, C₁₋₆ alicyclic,        heterocyclic, aryl, biheterocyclic, biaryl, or biheteroaryl, or        heteroaryl, each optionally substituted by 1, 2 or 3 R^(W2);    -   each R^(W2) is independently H, halo, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more F), C1-6        heteroalkyl (linear, branched, optionally substituted),        —OR^(W2A), OC₁₋₃ alkyl (optionally substituted by 1 or more —F),        C₃₋₆ cycloalkyl, C₄₋₆ cycloheteroalkyl, C₁₋₆ alkyl (optionally        substituted), C₁₋₆ alicyclic (optionally substituted),        heterocyclic (optionally substituted), aryl (optionally        substituted), or heteroaryl (optionally substituted), bicyclic        heteroaryl or aryl, OH, NH₂, NR^(Y1)R^(Y2), CN; and    -   R^(W2A) is H, C₁₋₆ alkyl (linear, branched), or C1-6 heteroalkyl        (linear, branched), each optionally substituted by a cycloalkyl,        cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or        OC₁₋₃alkyl.

In any aspect or embodiment described herein, an androgen receptorbinding moiety has a structure of:

wherein:

-   -   W¹ is

-   -   each R₂₂ is independently H or —CN;    -   each R₂₃ is independently H, halo, or —CF₃;    -   Y³ is a bond or O;    -   Q is a 4 member ring, optionally substituted with 0-4 R^(Q),        each R^(Q) is independently H or methyl;    -   Y4 is a bond or NH;    -   Y5 is a bond, a C═O, or a C═S; and    -   each W² is independently a bond, C1-6 aryl or heteroaryl, each        optionally substituted by 1, 2 or 3 R^(W2), each R^(W2) is        independently H, halo, a 6 member alicyclic ring with 1 or 2        heteroatoms or a 5 member aromatic ring with 1 or 2 or 3        heteroatoms.

In any aspect or embodiment described herein, W² is selected from thegroup consisting of:

In any aspect or embodiment described herein, the W² is covalentlycoupled to one or more ULM or CLM groups, or a linker to which isattached one or more ULM or CLM groups as described herein.

In any aspect or embodiment described herein, W¹ is selected from thegroup consisting of:

In any aspect or embodiment described herein, an androgen binding moietyhas a structure of:

wherein:

-   -   W¹ is aryl, independently substituted by 1 or more halo, CN;    -   Y³ are each independently a bond, NR^(Y2), CR^(Y1)R^(Y2), C═O;    -   Q is a 5 membered aromatic ring with 1 or 2 heteroatoms;    -   R^(Y1), R^(Y2) are each independently H, C₁₋₆ alkyl (linear,        branched);    -   W² is a bond, aryl, or heteroaryl, each optionally substituted        by 1, 2 or 3 R^(W2); and    -   each R^(W2) is independently H, halo, C₁₋₆ alkyl (optionally        substituted by 1 or more F), OC₁₋₃alkyl (optionally substituted        by 1 or more —F).

In any aspect or embodiment described herein, the W² is covalentlycoupled to one or more ULM or CLM groups, or a linker to which isattached one or more ULM or CLM groups as described herein.

In any aspect or embodiment described herein, W¹ is

wherein each R₂₂ is independently halo or CN; andeach R₂₃ is independently H or halo.

In any aspect or embodiment described herein, W¹ is selected from thegroup consisting of:

In any aspect or embodiment described herein, Q is

In any aspect or embodiment described herein, W² is

In any aspect or embodiment described herein, (Y³)₀₋₅ is

In any aspect or embodiment described herein, the ABM comprises astructure selected from, but not limited to the structures shown below,where a dashed line indicates the attachment point of a linker moiety ora ULM, such as a CLM:

wherein:

-   -   W¹ is

-   -   each R₂₂ is independently H or —CN;    -   each R₂₃ is independently H, halo, or —CF₃;    -   Y¹, Y² are each independently O or S;    -   Y³, Y⁴, Y⁵ are each independently a bond, O, NR^(Y2),        CR^(Y1)R^(Y2), C═O, C═S, SO, or SO₂;    -   R¹, R², are each independently H or a methyl group;    -   W² is a bond, C₁₋₆ aryl, or heteroaryl, each optionally        substituted by 1, 2 or 3 R^(W2); and    -   each R^(W2) is independently H, halo, C₁₋₆ alkyl (optionally        substituted by 1 or more F), C₃₋₆ cycloalkyl, C₄₋₆        cycloheteroalkyl, OC₁₋₃ alkyl (optionally substituted by 1 or        more —F).

In any aspect or embodiment described herein, the W² is covalentlycoupled to one or more ULM or CLM groups, or a linker to which isattached one or more ULM or CLM groups as described herein.

In any aspect or embodiment described herein, W¹ is selected from thegroup consisting of:

In any aspect or embodiment described herein, W₂ is selected from thegroup consisting of:

In any aspect or embodiment described herein, the ABM comprises astructure shown below, where a dashed line indicates the attachmentpoint of a linker moiety or a ULM or a CLM:

wherein:

-   -   W¹ is

-   -   each R₂₂ is independently H or —CN;    -   each R₂₃ is independently H, halo, or —CF₃;    -   Y³ is a bond or O;    -   Y⁴ is a bond or NH;    -   Y⁵ is a bond, C═O, C₁-C₆ heteroaryl, or C₁-C₆ aryl;    -   R¹, R², are each independently H, or C₁-C₆ alkyl (linear or        branched, optionally substituted by 1 or more halo, or C₁₋₆        alkoxyl);    -   W² is a bond, C₁₋₆ aryl, C1-6 heteroaryl, C₁₋₆ alicyclic, or        C1-6 heterocyclic, each optionally substituted by 1-10 R^(W2);        and    -   each R^(W2) is independently H, or halo; and

represents a bond that may be stereospecific ((R) or (S)) ornon-stereospecific.

In any of the embodiments described herein, the W² is covalently coupledto one or more ULM or CLM groups, or a linker to which is attached oneor more ULM or CLM groups as described herein.

In certain additional embodiments, W¹ is selected from the groupconsisting of:

In certain additional embodiments, W² is selected from the groupconsisting of:

In certain embodiments, the androgen receptor binding compound of ABM isselected from the group consisting of:

-   trans-2-Chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile;-   cis-2-Chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile;-   trans    6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridazine-3-carboxamide;-   trans tert-Butyl    N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate;-   trans    4-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide;-   trans    5-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrazine-2-carboxamide;-   trans    2-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine-5-carboxamide;-   4-Methoxy-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide;-   trans    1-(2-Hydroxyethyl)-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-1H-pyrazole-4-carboxamide;-   trans    6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide;-   trans    4-[(5-Hydroxypentyl)amino]-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide;    and-   trans tert-Butyl    2-({5-[(4-{[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)aminopentyl}oxy)acetate;    and-   N-((1r,3r)-3-(4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-methylbenzamide.

XIII. Compounds Targeting Estrogen Receptor (ER) ICI-182780

1. Estrogen Receptor Ligand

(Derivatized where “R” designates a site for linker group L or -(L-CLM)group attachment).

In any embodiment or aspect described herein, the PTM may be representedby the Formula PTM-I:

wherein:

-   -   X_(PTM) is O or C═O;    -   each of X_(PTM1) and X_(PTM2) is independently selected from N        or CH;    -   R_(PTM1) is independently selected from OH, O(CO)R_(PTM),        O-lower alkyl, wherein R_(PTM) is an alkyl or aryl group in the        ester;    -   at least one R_(PTM2), each independently selected from H, OH,        halogen, CN, CF₃, SO₂-alkyl, 0-lower alkyl;    -   at least one R_(PTM3), each independently selected from H,        halogen; and the dashed line indicates the site of attachment of        at least one linker, CLM, CLM′, PTM, PTM′, or a combination        thereof.

In any embodiment or aspect described herein, the PTM may be representedby the Formula PTM-I:

wherein:

-   -   X_(PTM) is O or C═O;    -   each of X_(PTM1) and X_(PTM2) is independently selected from N        or CH;    -   R_(PTM1) is independently selected from OH, O(CO)R_(PTM),        O-lower alkyl, wherein R_(PTM) is an alkyl or aryl group in the        ester;    -   each R_(PTM2) is independently selected from H, OH, halogen, CN,        CF₃, SO₂-alkyl, O-lower alkyl;    -   each R_(PTM3) is independently selected from H, halogen;    -   the PTM-I comprises as least one R_(PTM2), at least one        R_(PTM3), or a combination thereof on the respective rings; and    -   the dashed line indicates the site of attachment of at least one        linker, CLM, CLM′, PTM, PTM′, or a combination thereof.

In any embodiment or aspect described herein, PTM-I has at least one of:two R_(PTM2), two R_(PTM3), or a combination thereof.

In any embodiment or aspect described herein, the PTM may be representedby the Formula PTM-II:

wherein:

-   -   X_(PTM) is O or C═O;    -   each of X_(PTM1) and X_(PTM2) is independently selected from N        or CH;    -   R_(PTM1) is independently selected from OH, O(CO)R_(PTM),        O-lower alkyl, wherein R_(PTM) is an alkyl or aryl group in the        ester;    -   R_(PTM2) and R_(PTM4) are independently selected from H, OH,        halogen, CN, CF₃, SO₂-alkyl, 0-lower alkyl;    -   R_(PTM3) and R_(PTM5) are independently selected from H,        halogen; and    -   the dashed line indicates the site of attachment of at least one        linker, CLM, CLM′, PTM, PTM′, or a combination thereof.

In aspect or embodiment described herein, O(CO)R_(PTM) functions as aprodrug of the corresponding phenol in Formula PTM-I or PTM-II.

In any embodiment or aspect described herein, the O-lower alkyl of PTM-Ior PTM-II an alkyl chain with carbon number 1 to 3.

In aspect or embodiment described herein, the present disclosureprovides a compound or PTM of Formula (I_(PTM)):

wherein:

-   -   each X_(PTM) is independently CH, N;    -   indicates the site of attachment of at least one linker, CLM,        CLM′, PTM, PTM′, or a combination thereof;    -   each R_(PTM1) is independently OH, halogen, O(CO)R_(PTM), where        R_(PTM) is alkyl or cycloalkyl group with 1 to 6 carbons or aryl        groups, substitution can be mono-, di- or tri-substituted;    -   each R_(PTM2) is independently H, halogen, CN, CF₃, alkoxy,        substitution can be mono- or di-substitution; and    -   each R_(PTM3) is independently H, halogen, substitution can be        mono- or di-substitution.

In any aspect or embodiment described herein, the PTM is represented bythe Formula (II_(PTM)):

wherein:

-   -   X_(PTM) is CH, N;    -   indicates the site of attachment of at least one linker, CLM,        CLM′, PTM, PTM′, ULM, an ILM, a VLM, MLM, a ULM′, a ILM′, a        VLM′, a MLM′, or a combination thereof;    -   each R_(PTM1) is independently OH, halogen (e.g., F);    -   each R_(PTM2) is independently H, halogen (e.g., F), CF₃,        substitution can be mono- or di-substitution; and    -   each R_(PTM3) is independently halogen (e.g. F), substitution        can be mono- or di-substitution.

In certain embodiments, at least one of:

-   -   X_(PTM) of Formula (II_(PTM)) is CH;    -   R_(PTM1) of Formula (II_(PTM)) is OH;    -   R_(PTM2) of Formula (II_(PTM)) is H;    -   each R_(PTM3) of Formula (II_(PTM)) is independently H or F; or    -   a combination thereof.

XIV. Compounds Targeting Thyroid Hormone Receptor (TR)

1. Thyroid Hormone Receptor Ligand (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-CLM)group attachment and MOMO indicates a methoxymethoxy group).

XV. Compounds Targeting HIV Protease

1. Inhibitor of HIV Protease (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-CLM)group attachment). See, J. Med. Chem. 2010, 53, 521-538.

2. Inhibitor of HIV Protease

(Derivatized where “R” designates a potential site for linker group L or-(L-CLM) group attachment). See, J. Med. Chem. 2010, 53, 521-538.

XVI. Compounds Targeting HIV Integrase

1. Inhibitor of HIV Integrase (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-CLM)group attachment). See, J. Med. Chem. 2010, 53, 6466.

2. Inhibitor of HIV Integrase (derivatized)

3. Inhibitor of HIV integrase Isetntress (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-CLM)group attachment). See, J. Med. Chem. 2010, 53, 6466.

XVII. Compounds Targeting HCV Protease

1. Inhibitors of HCV Protease (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-CLM)group attachment).

XVIII. Compounds Targeting Acyl-Protein Thioesterase-1 and -2 (APT1 andAPT2)

1. Inhibitor of APT1 and APT2 (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-CLM)group attachment). See, Angew. Chem. Int. Ed. 2011, 50, 9838-9842, whereL is a linker group as otherwise described herein and said CLM group isas otherwise described herein such that -(L-CLM) binds the CLM group toa PTM group as otherwise described herein.

VIV. Compound Targeting Tau Protein

In any aspect or embodiment described herein, the PTM may include a Tauprotein binding moieties. For example, the PTM may be represented byFormula I, Formula II, Formula III, Formula IV, Formula V, Formula VI,Formula, VII, Formula, VIII, Formula IX, Formula X, or Formula XI:

wherein:

-   -   A, B, C, D, E, and F are independently selected from an        optionally substituted 5- or 6-membered aryl or heteroaryl ring,        an optionally substituted 4- to 7-membered cycloalkyl or a        heterocycloalkyl, where contact between circles indicates ring        fusion; and    -   L_(PTM) is selected from a bond, an alkyl, an alkenyl or an        alkynyl, optionally interrupted by one or more rings (i.e.,        cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or        more functional groups selected from the groups —O—, —S—, —NR¹        _(PTM)— (where R¹ _(PTM) is selected from H or alkyl), —N═N—,        —S(O)—, —SO₂—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO₂—, —NHC(O)NH—,        —NHC(O)O—, or —OC(O)NH—, wherein the said functional group are        optionally located at either end of the linker.

In any aspect or embodiment described herein, aryl and heteroaryl ringsof A, B, C, D, E, and F of PTM are optionally substituted with 1-3substituents each independently selected from alkyl, alkenyl, haloalkyl,halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino,dialkylamino, acylamino, trifluoromethyl, and cyano, wherein the saidalkyl and alkenyl groups are further optionally substituted.

In any aspect or embodiment described herein, the rings of at least oneof A, B, C, F, or a combination thereof is selected from optionallysubstituted 5- or 6-membered aryl or heteroaryl rings;

In any aspect or embodiment described herein, the PTM has the chemicalstructure of Formula I, wherein:

-   -   A, B and C rings are independently 5- or 6-membered fused aryl        or heteroaryl rings;    -   L_(PTM) is selected from a bond or an alkyl, and    -   D is selected from a 6-membered aryl, heteroaryl or        heterocycloalkyl, wherein A, B, C and D are optionally        substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy,        amino, alkylamino, dialkylamino or cyano.

In any aspect or embodiment described herein, The PTM has the chemicalstructure of Formula I, wherein:

-   -   A and C are a phenyl or a 6-membered heteroaryl ring;    -   B is a 5-membered heteroaryl ring;    -   L_(PTM) is a bond; and    -   D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl        ring;    -   wherein each A, B, C and D is optionally independently        substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy,        amino, dialkylamino or cyano, and wherein a nitrogen atom of any        of the A, B, C and D rings is not directly connected to a        heteroatom or to a carbon atom, to which another heteroatom is        directly attached.

In any aspect or embodiment described herein, the PTM has the chemicalstructure of Formula III or IV, wherein A, B and C are 5- or 6-memberedfused aryl or heteroaryl rings, L_(PTM) is selected from a bond or analkyl, and D and E are 5- or 6-membered fused aryl or heteroaryl rings,wherein A, B, C, D and E are optionally substituted with alkyl,haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino orcyano.

In any aspect or embodiment described herein, the PTM is represented byfollowing chemical structure:

wherein:

-   -   R¹, R² and R³ are independently selected from H, methyl, ethyl,        2-fluoroethyl and 2,2,2-trifluoroethyl;    -   R⁴ and R⁵ are independently selected from H, methyl, ethyl and        halogen; and    -   R⁶ is 1 to 2 substituents independently selected from H, methyl,        ethyl and halogen, wherein the PTM is coupled to a ULM via L.

In any of the aspects or embodiments described herein, the PTM iscovalently coupled to one or more ULM (VLM or CLM) groups, or a linkerto which is attached one or more ULM (VLM or CLM) groups as describedherein.

In any aspect or embodiment described herein, PTM is represented bychemical structure:

wherein:

-   -   R¹, R² and R³ are independently selected from H, optionally        substituted alkyl, methyl, ethyl, 2-fluoroethyl and        2,2,2-trifluoroethyl; and    -   R⁷, R⁸, R⁹ and R¹⁰ are 1 to 8 substituents independently        selected from H, optionally substituted alkyl, haloalkyl,        halogen, hydroxyl, alkoxy, amino, dialkylamino, acylamino,        trifluoromethyl or cyano, and wherein the PTM is coupled to a        ULM (VLM or CLM) via L.

In any aspect or embodiment described herein, PTM is represented bychemical structure:

In any aspect or embodiment described herein, the linker attachmentpoint to PTM is as indicated by the dotted line:

Therapeutic Compositions

Pharmaceutical compositions comprising combinations of an effectiveamount of at least one bifunctional compound as described herein, andone or more of the compounds otherwise described herein, all ineffective amounts, in combination with a pharmaceutically effectiveamount of a carrier, additive or excipient, represents a further aspectof the present disclosure.

The present disclosure includes, where applicable, the compositionscomprising the pharmaceutically acceptable salts, in particular, acid orbase addition salts of compounds as described herein. The acids whichare used to prepare the pharmaceutically acceptable acid addition saltsof the aforementioned base compounds useful according to this aspect arethose which form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3naphthoate)] salts, among numerous others.

Pharmaceutically acceptable base addition salts may also be used toproduce pharmaceutically acceptable salt forms of the compounds orderivatives according to the present disclosure. The chemical bases thatmay be used as reagents to prepare pharmaceutically acceptable basesalts of the present compounds that are acidic in nature are those thatform non-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (eg.,potassium and sodium) and alkaline earth metal cations (eg, calcium,zinc and magnesium), ammonium or water-soluble amine addition salts suchas N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines, amongothers.

The compounds as described herein may, in accordance with thedisclosure, be administered in single or divided doses by the oral,parenteral or topical routes. Administration of the active compound mayrange from continuous (intravenous drip) to several oral administrationsper day (for example, Q.I.D.) and may include oral, topical, parenteral,intramuscular, intravenous, sub-cutaneous, transdermal (which mayinclude a penetration enhancement agent), buccal, sublingual andsuppository administration, among other routes of administration.Enteric coated oral tablets may also be used to enhance bioavailabilityof the compounds from an oral route of administration. The mosteffective dosage form will depend upon the pharmacokinetics of theparticular agent chosen as well as the severity of disease in thepatient. Administration of compounds according to the present disclosureas sprays, mists, or aerosols for intra-nasal, intra-tracheal orpulmonary administration may also be used. The present disclosuretherefore also is directed to pharmaceutical compositions comprising aneffective amount of compound as described herein, optionally incombination with a pharmaceutically acceptable carrier, additive orexcipient. Compounds according to the present disclosure ion may beadministered in immediate release, intermediate release or sustained orcontrolled release forms. Sustained or controlled release forms arepreferably administered orally, but also in suppository and transdermalor other topical forms. Intramuscular injections in liposomal form mayalso be used to control or sustain the release of compound at aninjection site.

The compositions as described herein may be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers and mayalso be administered in controlled-release formulations.Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions as described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions as described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions as described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions as described herein maybe administered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient, which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions as described herein may also beadministered topically. Suitable topical formulations are readilyprepared for each of these areas or organs. Topical application for thelower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-acceptable transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. In certain preferred aspects of the invention, the compounds maybe coated onto a stent which is to be surgically implanted into apatient in order to inhibit or reduce the likelihood of occlusionoccurring in the stent in the patient.

Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions as described herein may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of compound in a pharmaceutical composition as describedherein that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host and diseasetreated, the particular mode of administration. Preferably, thecompositions should be formulated to contain between about 0.05milligram to about 750 milligrams or more, more preferably about 1milligram to about 600 milligrams, and even more preferably about 10milligrams to about 500 milligrams of active ingredient, alone or incombination with at least one other compound according to the presentdisclosure.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

A patient or subject in need of therapy using compounds according to themethods described herein can be treated by administering to the patient(subject) an effective amount of the compound according to the presentdisclosure including pharmaceutically acceptable salts, solvates orpolymorphs, thereof optionally in a pharmaceutically acceptable carrieror diluent, either alone, or in combination with other knownerythropoiesis stimulating agents as otherwise identified herein.

These compounds can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, including transdermally, in liquid, cream,gel, or solid form, or by aerosol form.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount for the desired indication, withoutcausing serious toxic effects in the patient treated. A preferred doseof the active compound for all of the herein-mentioned conditions is inthe range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kgper day, more generally 0.5 to about 25 mg per kilogram body weight ofthe recipient/patient per day. A typical topical dosage will range from0.01-5% wt/wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing less than 1 mg, 1 mgto 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosageform. An oral dosage of about 25-250 mg is often convenient.

The active ingredient is preferably administered to achieve peak plasmaconcentrations of the active compound of about 0.00001-30 mM, preferablyabout 0.1-30 μM. This may be achieved, for example, by the intravenousinjection of a solution or formulation of the active ingredient,optionally in saline, or an aqueous medium or administered as a bolus ofthe active ingredient. Oral administration is also appropriate togenerate effective plasma concentrations of active agent.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound or its prodrug derivative can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a dispersing agent such as alginicacid, Primogel, or corn starch; a lubricant such as magnesium stearateor Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or entericagents.

The active compound or pharmaceutically acceptable salt thereof can beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active compound or pharmaceutically acceptable salts thereof canalso be mixed with other active materials that do not impair the desiredaction, or with materials that supplement the desired action, such aserythropoietin stimulating agents, including EPO and darbapoietin alfa,among others. In certain preferred aspects of the invention, one or morecompounds according to the present disclosure are coadministered withanother bioactive agent, such as an erythropoietin stimulating agent ora would healing agent, including an antibiotic, as otherwise describedherein.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

Liposomal suspensions may also be pharmaceutically acceptable carriers.These may be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811 (which isincorporated herein by reference in its entirety). For example, liposomeformulations may be prepared by dissolving appropriate lipid(s) (such asstearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline,arachadoyl phosphatidyl choline, and cholesterol) in an inorganicsolvent that is then evaporated, leaving behind a thin film of driedlipid on the surface of the container. An aqueous solution of the activecompound are then introduced into the container. The container is thenswirled by hand to free lipid material from the sides of the containerand to disperse lipid aggregates, thereby forming the liposomalsuspension.

Therapeutic Methods

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Disease states or conditions,including cancer, which may be treated using compounds according to thepresent disclosure are set forth hereinabove.

The description provides therapeutic compositions as described hereinfor effectuating the degradation of proteins of interest for thetreatment or amelioration of a disease, e.g., cancer. In certainadditional embodiments, the disease is multiple myeloma. As such, inanother aspect, the description provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bifunctional compoundas described herein comprising, e.g., a CLM and a PTM, preferably linkedthrough a linker moiety, as otherwise described herein, wherein the CLMis coupled to the PTM and wherein the CLM recognizes a ubiquitin pathwayprotein (e.g., an ubiquitin ligase, preferably an E3 ubiquitin ligasesuch as, e.g., cereblon) and the PTM recognizes the target protein suchthat degradation of the target protein will occur when the targetprotein is placed in proximity to the ubiquitin ligase, thus resultingin degradation/inhibition of the effects of the target protein and thecontrol of protein levels. The control of protein levels afforded by thepresent disclosure provides treatment of a disease state or condition,which is modulated through the target protein by lowering the level ofthat protein in the cell, e.g., cell of a patient. In certainembodiments, the method comprises administering an effective amount of acompound as described herein, optionally including a pharmaceuticallyacceptable excipient, carrier, adjuvant, another bioactive agent orcombination thereof.

In additional embodiments, the description provides methods for treatingor emeliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptableexcipient, carrier, adjuvant, another bioactive agent or combinationthereof, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

In another embodiment, the present disclosure is directed to a method oftreating a human patient in need for a disease state or conditionmodulated through a protein where the degradation of that protein willproduce a therapeutic effect in that patient, the method comprisingadministering to a patient in need an effective amount of a compoundaccording to the present disclosure, optionally in combination withanother bioactive agent. The disease state or condition may be a diseasecaused by a microbial agent or other exogenous agent such as a virus,bacteria, fungus, protozoa or other microbe or may be a disease state,which is caused by overexpression of a protein, which leads to a diseasestate and/or condition

The term “disease state or condition” is used to describe any diseasestate or condition wherein protein dysregulation (i.e., the amount ofprotein expressed in a patient is elevated) occurs and where degradationof one or more proteins in a patient may provide beneficial therapy orrelief of symptoms to a patient in need thereof. In certain instances,the disease state or condition may be cured.

Disease states of conditions which may be treated using compoundsaccording to the present disclosure include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease,(PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachsdisease, Turner syndrome.

Further disease states or conditions which may be treated by compoundsaccording to the present disclosure include Alzheimer's disease,Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa,Anxiety disorder, Atherosclerosis, Attention deficit hyperactivitydisorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronicobstructive pulmonary disease, Crohn's disease, Coronary heart disease,Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type2, Epilepsy, Guillain-Barré syndrome, Irritable bowel syndrome, Lupus,Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke,Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

Still additional disease states or conditions which can be treated bycompounds according to the present disclosure includeaceruloplasminemia, Achondrogenesis type II, achondroplasia,Acrocephaly, Gaucher disease type 2, acute intermittent porphyria,Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency,adenylosuccinate lyase deficiency, Adrenogenital syndrome,Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency,Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema,amyotrophic lateral sclerosis Alström syndrome, Alexander disease,Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabrydisease, androgen insensitivity syndrome, Anemia Angiokeratoma CorporisDiffusum, Angiomatosis retinae (von Hippel-Lindau disease) Apertsyndrome, Arachnodactyly (Marfan syndrome), Stickler syndrome,Arthrochalasis multiplex congenital (Ehlers-Danlos syndrome #arthrochalasia type) ataxia telangiectasia, Rett syndrome, primarypulmonary hypertension, Sandhoff disease, neurofibromatosis type II,Beare-Stevenson cutis gyrata syndrome, Mediterranean fever, familial,Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dube syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Kennedy's syndrome,Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome,Jackson-Weiss syndrome, Kidney diseases, including hyperoxaluria,Klinefelter's syndrome, Kniest dysplasia, Lacunar dementia,Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies), TreacherCollins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease),Vision impairment and blindness (Alstr-m syndrome), Vrolik disease,Waardenburg syndrome, Warburg Sjo Fledelius Syndrome,Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, WolffPeriodic disease, Weissenbacher-Zweymüller syndrome and Xerodermapigmentosum, among others.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Exemplary cancers which may be treated by the presentcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present disclosure include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

The term “bioactive agent” is used to describe an agent, other than acompound according to the present disclosure, which is used incombination with the present compounds as an agent with biologicalactivity to assist in effecting an intended therapy, inhibition and/orprevention/prophylaxis for which the present compounds are used.Preferred bioactive agents for use herein include those agents whichhave pharmacological activity similar to that for which the presentcompounds are used or administered and include for example, anti-canceragents, antiviral agents, especially including anti-HIV agents andanti-HCV agents, antimicrobial agents, antifungal agents, etc.

The term “additional anti-cancer agent” is used to describe ananti-cancer agent, which may be combined with compounds according to thepresent disclosure to treat cancer. These agents include, for example,everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib,GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107,TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457,MLN₈O₅₄, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFRinhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, aPARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TKinhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKTinhibitor, an mTORC1/2 inhibitor, a JAK/STAT inhibitor, a checkpoint-1or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase (mek)inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib,nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu,nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin,tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab,ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490,cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402,lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel,atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil,vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,Ionafarnib, BMS -214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor -freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

The term “anti-HIV agent” or “additional anti-HIV agent” includes, forexample, nucleoside reverse transcriptase inhibitors (NRTI), othernon-nucloeoside reverse transcriptase inhibitors (i.e., those which arenot representative of the present disclosure), protease inhibitors,fusion inhibitors, among others, exemplary compounds of which mayinclude, for example, 3TC (Lamivudine), AZT (Zidovudine), (−)-FTC, ddl(Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA),D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP(Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavirmesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV(Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors suchas T20, among others, fuseon and mixtures thereof, including anti-HIVcompounds presently in clinical trials or in development.

Other anti-HIV agents which may be used in coadministration withcompounds according to the present disclosure include, for example,other NNRTI's (i.e., other than the NNRTI's according to the presentdisclosure) may be selected from the group consisting of nevirapine(BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781(N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide),etravirine (TMC125), Trovirdine (Ly300046.HCl), MKC-442 (emivirine,coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278),MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl3′,3′-dichloro-4′,4″-dimethoxy-5′,5″-bis(methoxycarbonyl)-6,6-diphenylhexenoate),Methyl3-Bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate(Alkenyldiarylmethane analog, Adam analog),(5-chloro-3-(phenylsulfinyl)-2′-indolecarboxamide), AAP-BHAP (U-104489or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E),aurin tricarboxylic acid (SD-095345),1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[3-(Ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine,1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[[5-(Methylsulfonyloxy)-2-indolylcarbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,U88204E, Bis(2-nitrophenyl)sulfone (NSC 633001), Calanolide A(NSC675451), Calanolide B,6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961,E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M(1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), InophyllumP, L-737,126, Michellamine A (NSC650898), Michellamine B (NSC649324),Michellamine F,6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil,6-(3,5-Dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU(NSC 648400), Oltipraz(4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione),N-{2-(2-Chloro-6-fluorophenethyl]-N′-(2-thiazolyl)thiourea (PETT Cl, Fderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-bromopyridyl)]thiourea {PETTderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-methylpyridyl)]thiourea {PETTPyridyl derivative),N-[2-(3-Fluorofuranyl)ethyl]-N′-[2-(5-chloropyridyl)]thiourea,N-[2-(2-Fluoro-6-ethoxyphenethyl)]—N′-[2-(5-bromopyridyl)]thiourea,N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea (LY-73497), L-697,639,L-697,593, L-697,661,342-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pypridin-2(1H)-thione(2-Pyridinone Derivative),3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pypridin-2(1H)-thione,R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720,Suramin Sodium, TBZ (Thiazolobenzimidazole, NSC 625487),Thiazoloisoindol-5-one,(+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one,Tivirapine (R86183), UC-38 and UC-84, among others.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastric juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts, among numerousother acids and bases well known in the pharmaceutical art. Sodium andpotassium salts are particularly preferred as neutralization salts ofthe phosphates according to the present disclosure.

The term “pharmaceutically acceptable derivative” is used throughout thespecification to describe any pharmaceutically acceptable prodrug form(such as an ester, amide other prodrug group), which, uponadministration to a patient, provides directly or indirectly the presentcompound or an active metabolite of the present compound.

General Synthetic Approach

The synthetic realization and optimization of the bifunctional moleculesas described herein may be approached in a step-wise or modular fashion.For example, identification of compounds that bind to the targetmolecules can involve high or medium throughput screening campaigns ifno suitable ligands are immediately available. It is not unusual forinitial ligands to require iterative design and optimization cycles toimprove suboptimal aspects as identified by data from suitable in vitroand pharmacological and/or ADMET assays. Part of the optimization/SARcampaign would be to probe positions of the ligand that are tolerant ofsubstitution and that might be suitable places on which to attach thelinker chemistry previously referred to herein. Where crystallographicor NMR structural data are available, these can be used to focus such asynthetic effort.

In a very analogous way one can identify and optimize ligands for an E3Ligase, i.e. ULMs/CLMs.

With PTMs and ULMs (e.g. CLMs) in hand one skilled in the art can useknown synthetic methods for their combination with or without a linkermoiety. Linker moieties can be synthesized with a range of compositions,lengths and flexibility and functionalized such that the PTM and ULMgroups can be attached sequentially to distal ends of the linker. Thus alibrary of bifunctional molecules can be realized and profiled in invitro and in vivo pharmacological and ADMET/PK studies. As with the PTMand ULM groups, the final bifunctional molecules can be subject toiterative design and optimization cycles in order to identify moleculeswith desirable properties.

ABBREVIATIONS

ACN: acetonitrileAcOH, acetic acidADDP: 1,1′-(azodicarbonyl)dipiperidineaq., aqueousBAST: N,N-bis(2-methoxyethyl)aminosulfur trifluorideBINAP, 2,2′-bis(diphenylphosphino)-1,1′-binaphthaleneBoc, tert-butoxycarbonylBoc₂O, di-tert-butyl decarbonateBOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphateBPO: benzoyl peroxide

Cbz: Carbonylbezyloxy

CDCl₃, deuteriochloroformCD3OD, deuteriomethanolCH₃CN, acetonitrileCH₃OH, methanolCsF, cesium fluorideCs₂CO₃, cesium carbonateCu(OAc)₂, copper (II) acetateCy₂NMe, dicyclohexylmethylamineDAST: diethylaminosulfur trifluorideDBE: 1,2-dibromoethaneDCM: dichloromethaneDEAD: diethyl azodicarboxylateDIAD: diisopropyl azodicarboxylateDIBAL: disiobutylaluminium hydrideDIEA or DIPEA: diisopropylethylamine

DMA: N,N-dimethylacetamide DMAP, N,N-dimethylaminopyridine DMF:N,N-dimethylformamide

DMP: Dess-Martin periodinaneDMSO, dimethylsulfoxideDMSO-d₆, hexadeuterodimethyl sulfoxideEA: ethyl acetateEDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideEt₂NH, diethylamineEtOAc or EA, ethyl acetateHCl, hydrochloric acidH₂O, waterHBTU: N,N,N′N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphateHMDS: bis9trimethylsilyl)amineHMPA: hexamethylphosphoramideHPLC, high performance liquid chromatographyIBX, 2-iodoxybenzoic acidKOAc, potassium acetateLCMS, liquid chromatography/mass spectrometryLDA: lithium diisopropylamideLiOH, lithium hydroxideMCPBA: meta-chloroperoxybenzoic acidMeOH, methanolMsCl: methanesulfonyl chlorideM.W: microwaveN₂, nitrogenNaH, sodium hydrideNaBH₃CN, sodium cyanoborohydrideNaBH(OAc)₃, sodium triacetoxyborohydrideNaCl, sodium chlorideNaHCO₃, sodium bicarbonateNaI, sodium iodideNa₂SO₄, sodium sulfate

NB S: N-bromosuccinimide

n-BuLi, n-butyllithiumNH₃, ammoniaNH₄Cl, ammonium chlorideNH₂OH HCl, hydroxylamine hydrochloride

NMP, N-methylpyrrolidone

NMR, nuclear magnetic resonanceO₂, oxygenPCC: pyridinium chlorochromatePd-118 or Pd(dtpf)Cl₂: 1,1′-bis(di-tert-butylphosphino)ferrocenedichloropalladiumPd(aMPhos)C12,bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladiumPd(dppf)Cl₂: 1,1′-bis(diphenylphosphino)ferrocene dichloropalladiumPd(dba)₂: bis(dibenzylideneacetone)palladiumPd(OH)₂, palladium hydroxidePd(PPh₃)₄, tetrakis(triphenylphosphine)palladium(O)PE, petroleum etherPh₃P, triphenylphosphinePPTS: pyridium p-tolunesulfonatePTSA: p-toluenesulfonic acidPy, pyridinePyBOP, (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphatert, room temperatureRuPhos-Pd-G3: XPhos-Pd-G3:[(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonateRuPhos-Pd-G2:Chloro[(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)SFC: supercritical fluid chromatographyTBAF, tetra-n-butylammonium fluorideTBDPSCl, tert-butyldiphenylsilyl chlorideTBS, tert-butyldimethylsilyltBuOK, potassium tert-butoxide[tBu₃PH]BF₄, tri-tert-butyl phosphonium tetrafluoroboratet-BuXPhos-Pd-G3:[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonateTEA: trimethylamineTFA: trifluoroacetic acidTLC: thin layer chromatographyTMP: 2,2,6,6-tetramethylpiperidineTEMPO: 2,2,6,6-tetramethylpiperidine-N-oxideTMS OTf, trimethylsilyl trifluoromethanesulfonateTosCl or TsCl: p-toluenesulfonyl chlorideTsCl, p-toluenesufonyl chlorideTsOH: p-toluenesulfonic acidXantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneXPhos: 2-dicyclohexylphosphino-2′4′6′-triisopropylbiphenylXPhos-Pd-G3:[(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate12354-85-7: bis(pentamethylcyclopentadienylrhodium dichloride)

A. Exemplary Synthetic Schemes for Exemplary Estrogen Receptor BindingMoiety Based Compounds

Synthetic scheme A-1, A-2 through A-5, A-6, and A-7 described the routesused in the preparation of CRBN ligands, as well as CRBN ligands withpartial linker moieties connected.

General Synthetic Scheme A-1 to Prepare Intermediate.

General Synthetic Scheme A-2 to Prepare Intermediate.

General Synthetic Scheme A-3 to Prepare Intermediate.

General Synthetic Scheme A-4 to Prepare Intermediate.

General Synthetic Scheme A-5 to Prepare Intermediate.

General Synthetic Scheme A-6 to Prepare Intermediate.

General Synthetic Scheme A-7 to Prepare Intermediate.

Synthetic schemes A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16,and A-17, described the routes used in the preparation of representativechimeric compounds claimed in this application.

General Synthetic Scheme A-8 to Prepare Claimed Compounds.

General Synthetic Scheme A-9 to Prepare Claimed Compounds.

General Synthetic Scheme A-10 to Prepare Claimed Compounds.

General Synthetic Scheme A-11 to Prepare Claimed Compounds.

General Synthetic Scheme A-12 to Prepare Claimed Compounds.

General Synthetic Scheme A-13 to Prepare Claimed Compounds.

General Synthetic Scheme A-14 to Prepare Claimed Compounds.

General Synthetic Scheme A-15 to Prepare Claimed Compounds.

General Synthetic Scheme A-16 to Prepare Claimed Compounds.

General Synthetic Scheme A-17 to Prepare Claimed Compounds.

Exemplary Synthesis of Exemplary Compound 2:3-{5-[4-(5-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenoxy}pentyl)piperazin-1-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dioneStep 1: Preparation of 5-bromopentanal

To a solution of oxalyl dichloride (9.12 g, 72 mmol, 6 mL, 4.00 eq) indichloromethane (50 mL) was added a solution of dimethylsulfoxide (5.61g, 72 mmol, 4.00 eq) in dichloromethane (10 mL) at −70° C. over 30 min,and then 5-bromopentan-1-ol (3.00 g, 18 mmol, 1.00 eq) was added atbelow −60° C. The resulting mixture was stirred at −70° C. for 1 hr.Thin-layer chromatography (petroleum ether:ethyl acetate=10:1) showedthe reaction was complete. Triethylamine (14.54 g, 144 mmol, 20 mL, 8.00eq) was added into the mixture and the reaction was stirred at −60° C.for 30 min. The mixture was poured into water (20 mL) and stirred for 1min. The aqueous phase was extracted with dichloromethane (20 mL×3). Thecombined organic phase was washed with brine (20 mL×2), dried withanhydrous sodium sulfate, filtered and concentrated in vacuum. Theresidue was directly used for the next step without furtherpurification. 5-bromopentanal (2.80 g, 17 mmol, 94% yield) was obtainedas a colorless oil.

Step 2: Preparation of 5-bromo-1,1-dimethoxypentane

To a solution of 5-bromopentanal (2.80 g, 16.97 mmol, 1.00 eq) inmethanol (50 mL) was added trimethoxymethane (9.00 g, 85 mmol, 9 mL,5.00 eq) and 4-methylbenzenesulfonic acid hydrate (161 mg, 0.85 mmol,0.05 eq) at 25° C. The resulting mixture was stirred at 25° C. for 16hr. Thin-layer chromatography (petroleum ether:ethyl acetate=10:1)showed a major new spot. The mixture was poured into water (40 mL) andstirred for 1 min. The aqueous phase was extracted with ethyl acetate(30 mL×3). The combined organic phase was washed with brine (20 mL×2),dried with anhydrous sodium sulfate, filtered and concentrated invacuum. The residue was purified by silica gel column chromatography(petroleum ether:ethyl acetate=15:1). 5-Bromo-1,1-dimethoxy-pentane(3.50 g, 16.58 mmol, 97% yield) was obtain as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 4.37 (t, J=5.6 Hz, 1H), 3.41 (s, 2H), 3.33 (s,6H), 1.95-1.84 (m, 2H), 1.67-1.59 (m, 2H), 1.54-1.45 (m, 2H).

Step 3: Preparation of(1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin

To a solution of 4-[(1R,2S)-6-benzyloxy-2-phenyl-tetralin-1-yl]phenol(500 mg, 1.23 mmol, 1.00 eq) in dimethylformamide (5 mL) was addedcesium carbonate (1.2 g, 3.69 mmol, 3.00 eq) and5-bromo-1,1-dimethoxy-pentane (390 mg, 1.84 mmol, 1.50 eq). The mixturewas stirred at 100° C. for 1 hour. The reaction mixture was diluted withwater (30 mL) and extracted with ethyl acetate (15 mL×2). The combinedorganic phase was washed with saturated brine (15 mL×2), dried withanhydrous sodium sulfate, filtered and concentrated in vacuum. Theresidue was purified by silica gel column chromatography (petroleumether:ethyl acetate=50:1 to 10:1) to give(1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin(500 mg, 0.93 mmol, 76% yield) as a white solid. LC/MS (ESI) m/z: 559.2[M+23]⁺, ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.45 (m, 2H), 7.44-7.38 (m, 2H),7.37-7.31 (m, 1H), 7.21-7.13 (m, 3H), 6.90-6.85 (m, 2H), 6.82 (dd,J=2.0, 7.2 Hz, 2H), 6.76 (dd, J=2.4, 8.4 Hz, 1H), 6.53 (d, J=8.8 Hz,2H), 6.32 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 4.38 (t, J=5.6 Hz, 1H), 4.25(d, J=4.8 Hz, 1H), 3.84 (t, J=6.4 Hz, 2H), 3.41-3.28 (m, 7H), 3.17-2.99(m, 2H), 2.28-2.13 (m, 1H), 1.87-1.71 (m, 3H), 1.69-1.60 (m, 2H),1.54-1.42 (m, 2H).

Step 4: Preparation of(1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol

To a solution of(1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin(500 mg, 0.93 mmol, 1.00 eq) in methanol (20 mL) and tetrahydrofuran (20mL) was added palladium on carbon (200 mg, 10% purity) under nitrogenatmosphere. The suspension was degassed and purged with hydrogen 3times. The mixture was stirred under hydrogen (15 psi) at 25° C. for 12h. The reaction mixture was filtered and the filter was concentrated togive (1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol(420 mg, crude) as a white solid. LC/MS (ESI) m/z: 469.1 [M+23]⁺.

Step 5: Preparation of5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal

To a solution of(1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol (420mg, 0.94 mmol, 1.00 eq) in tetrahydrofuran (75 mL) was added sulfuricacid (2 M in water, 18 mL, 40.00 eq). The mixture was stirred at 70° C.for 0.5 h. Thin layer chromatography (petroleum ether:ethyl acetate=3:1)showed the reaction was completed and a new spot formed. The reactionmixture was diluted with water (40 mL) and extracted with ethyl acetate(20 mL×2). The combined organic phase was washed with saturated sodiumbicarbonate (15 mL) and saturated brine (20 mL×2), dried with anhydroussodium sulfate, filtered and concentrated in vacuum to give5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal (370 mg,0.92 mmol, 98% yield) as a white solid.

Step 6: Preparation of tert-butyl4-(7-methoxy-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a mixture of 5-fluoro-7-methoxy-3H-isobenzofuran-1-one (1 g, 5.49mmol, 1 eq) and tert-butyl piperazine-1-carboxylate (2.05 g, 10.98 mmol,2 eq) in 1-methylpyrrolidin-2-one (6 mL) was addedN-ethyl-N-isopropylpropan-2-amine (2.84 g, 21.96 mmol, 3.83 mL, 4 eq) inone portion. The mixture was stirred at 100° C. for 12 hours. TLC (ethylacetate/petroleum ether=1/1, R_(f)=0.1) indicated a new spot formed. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (40 mL×2). The combined organic layers were washed with water(15 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=10/1 to 1:1). Tert-butyl4-(7-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (1 g,2.87 mmol, 52% yield) was obtained as a yellow solid. LC/MS (ESI) m/z:349.3 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 6.38 (s, 1H), 6.30 (s, 1H), 5.13(s, 2H), 3.99 (s, 3H), 3.62-3.59 (m, 4H), 3.42-3.35 (m, 4H), 1.48 (s,9H).

Step 7: Preparation of4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(hydroxymethyl)-6-methoxybenzoicAcid

To a mixture of tert-butyl4-(7-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (1 g,2.87 mmol, 1 eq) in methyl alcohol (10 mL) and tetrahydrofuran (10 mL)was added the solution of sodium hydroxide (459 mg, 11.48 mmol, 4 eq) inwater (2 mL). The mixture was stirred at 20° C. for 1 h. TLC (ethylacetate/petroleum ether=1/1, R_(f)=0) indicated a new spot formed. Thereaction mixture was concentrated under reduced pressure to removesolvent. The residue was diluted with water (20 mL) and extracted withethyl acetate (30 mL×2). The aqueous phase was adjusted to pH value to4-5 with hydrochloric acid (1.5 N), then filtered and the solid wascollected. The solid was used for the next step without furtherpurification.4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-6-methoxy-benzoicacid (700 mg, 1.68 mmol, 58% yield, 88% purity) was obtained as a whitesolid. LC/MS (ESI) m/z: 367.3 [M+1]⁺.

Step 8: Preparation of4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-6-methoxybenzoic Acid

To a mixture of4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-6-methoxy-benzoicacid (650 mg, 1.77 mmol, 1 eq) and in methyl alcohol (20 mL) was addedmanganese dioxide (1.54 g, 17.74 mmol, 10 eq) in one portion at 20° C.under nitrogen. The mixture was stirred at 50° C. for 12 hours. LC/MSshowed the reaction was completed and desired product was formed. Thereaction mixture was filtered and the solution was concentrated undervacuum. The reaction was used for the next step without furtherpurification.4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-formyl-6-methoxy-benzoic acid(600 mg, 1.65 mmol, 92% yield) was obtained as a yellow solid. LC/MS(ESI) m/z: 365.3 [M+1]⁺.

Step 9: Preparation of4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(((2,6-dioxopiperidin-3-yl)amino)methyl)-6-methoxybenzoicAcid

To a mixture of4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-6-methoxy-benzoic acid(600 mg, 1.65 mmol, 1 eq) and 3-aminopiperidine-2,6-dione (407 mg, 2.47mmol, 1.5 eq, HCl) in methyl alcohol (10 mL) was added sodium acetate(203 mg, 2.47 mmol, 1.5 eq) and sodium cyanoborohydride (310 mg, 4.94mmol, 3 eq) in one portion at 20° C. The mixture was stirred at 20° C.for 2 h. LC/MS showed the reaction was completed and desired product wasformed. The reaction mixture was concentrated under vacuum. The residuewas purified by reverse phase flash silica gel chromatography (120 gSepaFlash silica gel column, eluent of 0-60% acetonitrile in water witha flow rate of 30 mL/min).4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-6-methoxy-benzoicacid (300 mg, 0.63 mmol, 38% yield) was obtained as a white solid. LC/MS(ESI) m/z: 477.4 [M+1]⁺.

Step 10: Preparation of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazine-1-carboxylate

To a mixture of4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-6-methoxy-benzoicacid (300 mg, 0.63 mmol, 1 eq) in dichloromethane (10 mL) was addedN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (181 mg,0.94 mmol, 1.5 eq), N-hydroxybenzotrizole (128 mg, 0.94 mmol, 1.5 eq),and triethylamine (191 mg, 1.89 mmol, 3 eq). The mixture was stirred at20° C. for 1 h. LC/MS showed the reaction was completed and desiredproduct was formed. The reaction mixture was quenched by addition ofwater (15 mL), and then extracted with dichloromethane (40 mL×2). Thecombined organic layers were washed with brine (10 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by preparative TLC (dichloromethane: methylalcohol=10:1, R_(f)=0.60). Tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate(260 mg, 0.57 mmol, 90% yield) was obtained as a white solid. LC/MS(ESI) m/z: 459.4 [M+1]⁺.

Step 11: Preparation of3-(7-methoxy-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

To a mixture of tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate(300 mg, 0.65 mmol, 1 eq) in dioxane (10 mL) was added hydrogenchloride/dioxane (4 M, 17 mL, 105.81 eq) in one portion. The mixture wasstirred at 20° C. for 2 h. The reaction mixture was concentrated underreduced pressure to remove solvent. The residue was used for the nextstep without further purification.3-(7-Methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione(216 mg, 0.55 mmol, 83% yield, HCl salt) was obtained as a white solid.LC/MS (ESI) m/z: 359.2 [M+1]⁺; ¹H-NMR (400 MHz, MeOD) δ: 6.72 (s, 1H),6.60 (s, 1H), 5.08-5.04 (m, 1H), 4.36-4.35 (m, 2H), 3.92 (s, 3H),3.66-3.65 (m, 5H), 3.38-3.35 (m, 4H), 2.89-2.78 (m, 1H), 2.77-2.67 (m,1H), 2.45-2.42 (m, 1H), 2.14-2.14 (m, 1H).

Step 12: Preparation of3-{5-[4-(5-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenoxy}pentyl)piperazin-1-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione(Exemplary Compound 2)

To a mixture of3-(7-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dionehydrochloride (89 mg, 0.23 mmol) in methyl alcohol (5 mL) anddichloromethane (1 mL) was added sodium acetate (102 mg, 1.25 mmol, 5eq) in one portion at 20° C. The mixture was stirred at 20° C. for 1 h,then 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal(100 mg, 0.25 mmol, 1 eq) was added to the reaction mixture and stirredfor 1 h. Sodium cyanoborohydride (31 mg, 0.50 mmol, 2 eq) and aceticacid (0.05 mL) was added to the reaction mixture. The resulting solutionwas stirred at 20° C. for 5 h. LC/MS showed the reaction was completedand desired product was formed. The reaction mixture was concentratedunder reduced pressure to remove solvent. The residue was purified bypreparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobilephase: [water (0.05% HCl)-acetonitrile]; B %: 35%-55%, 7.8 min).3-[5-[4-[5-[4-[(1R,2S)-6-Hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(109.9 mg, 0.14 mmol, 56% yield, 100% purity, HCl salt) was obtained asa white solid. LC/MS (ESI) m/z: 743.7 [M+1]⁺; ¹H-NMR (400 MHz, DMSO-d6)δ10.93 (s, 1H), 10.56-10.43 (m, 1H), 9.18-9.13 (m, 1H), 7.16-7.13 (m,3H), 6.84-6.83 (d, J=6.4 Hz, 2H), 6.69 (s, 1H), 6.62-6.61 (m, 2H),6.55-6.52 (m, 3H), 6.28-6.26 (d, J=8.4 Hz, 2H), 4.99-4.97 (m, 1H),4.29-4.25 (m, 1H), 4.23-4.18 (m, 1H), 4.17-4.15 (m, 1H), 4.06-4.00 (m,2H), 3.85-3.83 (m, 5H), 3.56-3.53 (m, 1H), 3.34-3.33 (m, 4H), 3.10-3.02(m, 4H), 3.00-2.85 (m, 2H), 2.60-2.58 (m, 3H), 2.16-2.08 (m, 1H),1.91-1.88 (m, 1H), 1.76-1.69 (m, 5H), 1.43-1.41 (m, 2H).

Exemplary Synthesis of Exemplary Compound 3:3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dioneStep 1: Preparation of 5-bromo-4-iodo-3H-isobenzofuran-1-one

To a solution of 5-bromo-3H-isobenzofuran-1-one (50 g, 234.71 mmol, 1eq) in trifluoromethanesulfonic acid (680 g, 4.53 mol, 400 mL, 19.30 eq)was added 1-iodopyrrolidine-2,5-dione (55.45 g, 246.45 mmol, 1.05 eq) at0° C. in portions. The mixture was allowed to warm to 15° C. and heldfor 16 h. TLC (petroleum ether:ethyl acetate=5:1) showed no startingmaterial remained and two new spots (R_(f)=0.4, 0.5) formed. Thereaction mixture was poured into ice-water (1 L) and yellow solidprecipitated. The mixture was filtered and the filter cake was washedwith water. The filter cake was dissolved in ethyl acetate (500 mL) andthe resulting orange solution was dried over sodium sulfate. The mixturewas filtered and the filtrate was concentrated to afford a yellow solid.The residue was triturated with ethyl acetate (50 mL), filtered andwashed with ethyl acetate (10 mL×2).5-Bromo-4-iodo-3H-isobenzofuran-1-one (40 g, 118.02 mmol, 50% yield) wasobtained as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=8.0 Hz,1H), 7.77 (d, J=8.0 Hz, 1H), 5.10 (s, 2H).

Step 2: Preparation of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one

To a mixture of 5-bromo-4-iodo-3H-isobenzofuran-1-one (40 g, 118.02mmol, 1 eq), sodium hydroxide (23.60 g, 590.10 mmol, 5 eq) in water (400mL) and N,N-dimethylacetamide (200 mL) was added cuprous oxide (3.38 g,23.60 mmol, 2.4 mL, 0.2 eq). The reaction mixture was heated to 80° C.and held for 16 h. TLC (petroleum ether:ethyl acetate=1:1, R_(f)=0.3)showed the reaction was completed. The reaction mixture was poured into1N hydrochloride solution (400 mL) and extracted with ethyl acetate (400mL×2). The combined organic layers were concentrated and dissolved inethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate(150 mL), brine (150 mL) and then dried over sodium sulfate. The mixturewas filtered and the filtrate was concentrated to afford a residue. Theresidue was triturated with ethyl acetate (20 mL), filtered and washedwith ethyl acetate (10 mL) to give a solid. The filtrate was furtherconcentrated and triturated with ethyl acetate.5-Bromo-4-hydroxy-3H-isobenzofuran-1-one (14.5 g, 60.15 mmol, 50% yield,95% purity) was obtained as a white solid. ¹H NMR (400 MHz, DMSO) δ10.90 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 5.35 (s,2H).

Step 3: Preparation of 5-bromo-4-methoxy-3H-isobenzofuran-1-one

To a mixture of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one (3 g, 13.10mmol, 1 eq) in acetone (20 mL) was added iodomethane (17.5 g, 123.29mmol, 7.7 mL, 9.41 eq) and potassium carbonate (5.43 g, 39.30 mmol, 3eq). The mixture was stirred at 20° C. for 15 h. TLC (ethyl acetate:petroleum ether=1:3, R_(f)=0.37) indicated reaction was completed. Thereaction mixture was quenched by addition of water (10 mL), and thenextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with saturated sodium bicarbonate (10 mL×2), dried over sodiumsulfate, filtered and concentrated under reduced pressure.5-Bromo-4-methoxy-3H-isobenzofuran-1-one (2.9 g, 11.93 mmol, 91% yield)was obtained as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=8.0Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 5.44 (s, 2H), 4.00 (s, 3H).

Step 4: Preparation of tert-butyl4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate

A vial was charged with 5-bromo-4-methoxy-3H-isobenzofuran-1-one (500mg, 2.06 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (383 mg, 2.06mmol, 1 eq), tris(dibenzylideneacetone)dipalladium(O) (188 mg, 0.20mmol, 0.1 eq), XantPhos (119 mg, 0.20 mmol, 0.1 eq), potassium phosphate(873 mg, 4.11 mmol, 2 eq) and dioxane (5 mL). The mixture was purgedwith nitrogen and heated to 100° C. for 16 h. TLC (ethyl acetate:petroleum ether=1:3) showed reaction was complete. The mixture wasdiluted with ethyl acetate (30 mL) and washed with water (30 mL). Theaqueous layer was extracted with ethyl acetate (15 mL×3). The organiclayer was washed with brine (30 mL) and dried over sodium sulfate. Thecrude was purified by silica gel chromatography (ethyl acetate:petroleum ether=1:20 to 1:6). Tert-butyl4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (700mg, 2.01 mmol, 97% yield) was obtained as a yellow solid. LC/MS (ESI)m/z: 349.2 [M+1]⁺.

Step 5: Preparation of4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxylmethyl)-3-methoxy-benzoicAcid

To a solution of tert-butyl4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (700mg, 2.01 mmol, 1 eq) in tetrahydrofuran (4 mL) and water (4 mL) wasadded sodium hydroxide (401 mg, 10.05 mmol, 5 eq). The mixture wasstirred at 20° C. for 16 h. TLC (ethyl acetate: petroleum ether=1:2)showed reaction was complete. The mixture was adjusted to pH=4 withaqueous hydrochloric acid (1 M) and extracted with ethyl acetate (10ml×3). The organic layer was washed with brine (20 mL) and dried oversodium sulfate. The crude material was not further purified.4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-3-methoxy-benzoicacid (700 mg, crude) was obtained as a yellow solid.

Step 6: Preparation of4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-3-methoxybenzoic Acid

To a solution of4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-3-methoxy-benzoic acid (700 mg, 1.91 mmol, 1 eq) in dichloromethane (10 mL) wasadded manganese dioxide (2.49 g, 28.66 mmol, 15 eq). The mixture wasstirred at 20° C. for 1 h. TLC (dichloromethane:methanol=20:1) showedreaction was complete. The mixture was diluted with dichloromethane (10mL) and filtered through a pad of Celite. The filtrate was concentratedin vacuum. The crude product was purified by silica gel columnchromatography (dichloromethane:methanol=100:1 to 60:1).4-(4-(Tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-3-methoxybenzoic acid(300 mg, 0.82 mmol, 43% yield) was obtained as a pale yellow solid.

Step 7: Preparation of4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-3-methoxy-benzoic Acid

To a mixture of 3-aminopiperidine-2,6-dione (135 mg, 0.82 mmol, 1 eq,HCl salt) in methanol (2 mL) and dichloromethane (4 mL) was added sodiumacetate (270 mg, 3.29 mmol, 4 eq). The mixture was stirred at 20° C. for10 min, then4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-3-methoxy-benzoic acid(300 mg, 0.82 mmol, 1 eq) was added and the mixture was stirred for 10min. Sodium cyanoborohydride (103 mg, 1.65 mmol, 2 eq) was added and themixture was further stirred for 40 min. LCMS showed reaction wascomplete. The mixture was adjusted to pH=4-5 with aqueous hydrochloricacid solution (1 M) and extracted with ethyl acetate (10 mL×3). Theorganic layer was dried over sodium sulfate. The crude product was notfurther purified.4-(4-Tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-3-methoxy-benzoicacid (400 mg, crude) was obtained as a white solid. LC/MS (ESI) m/z:477.1 [M+1]⁺.

Step 8: Preparation of tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate

To a solution of4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-3-methoxy-benzoicacid (400 mg, 0.84 mmol, 1 eq) in dimethylformamide (5 mL) was addedo-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (383 mg, 1.01 mmol, 1.2 eq). The solution wasstirred for 10 min, then N,N-diisopropylethylamine (325 mg, 2.52 mmol, 3eq) was added. The solution was stirred at 20° C. for 20 min. LCMSshowed reaction was complete. The solution was diluted with ethylacetate (40 mL) and washed with water (30 mL×5) and brine (40 mL). Theorganic layer was dried over sodium sulfate. Tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate(400 mg, crude) was obtained as a pale yellow solid. LC/MS (ESI) m/z:459.1 [M+1]⁺.

Step 9: Preparation of 3-(4-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione

To a mixture of tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate(400 mg, 0.87 mmol, 1 eq) in dioxane (2 mL) was added hydrochloric acidin dioxane (4 M, 4 mL, 18.34 eq). The mixture was stirred at 20° C. for10 min and solvent was removed under vacuum.3-(4-Methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione(350 mg, crude, HCl salt) was obtained as a white solid. LC/MS (ESI)m/z: 359.1 [M+1]⁺.

Step 10: Preparation of3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dioneExemplary Compound 3

To a mixture of3-(4-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.25 mmol, 1 eq, HCl salt) in dichloromethane (4 mL) andmethanol (1 mL) was added sodium acetate (83 mg, 1.01 mmol, 4 eq). Themixture was stirred at 20° C. for 10 min. Then5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal (101 mg,0.25 mmol, 1.00 eq) was added and the mixture was stirred for 10 min.Sodium cyanoborohydride (31 mg, 0.51 mmol, 2 eq) was added to themixture and stirring was kept for 40 min. LCMS and TLC(dichloromethane:methanol=10:1) showed reaction was complete. Solventwas removed under vacuum. The crude product was purified by prep-TLC(dichloromethane:methanol=10:1).3[5-[4-[5-[4-[(1R,2S)-6-Hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(55 mg, 0.07 mmol, 29% yield, 99% purity) was obtained as a white solid.LC/MS (ESI) m/z: 743.3 [M+1]⁺; ¹H-NMR (400 MHz, DMSO-d6) δ 10.96 (s,1H), 9.12 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25-6.98 (m, 4H), 6.83 (d,J=6.8 Hz, 2H), 6.72-6.43 (m, 5H), 6.26 (d, J=8.6 Hz, 2H), 5.06 (dd,J=5.0, 13.2 Hz, 1H), 4.56-4.11 (m, 3H), 3.94-3.70 (m, 5H), 3.30-3.25 (m,1H), 3.21-2.77 (m, 8H), 2.64-2.55 (m, 5H), 2.46-2.26 (m, 2H), 2.16-1.94(m, 2H), 1.80-1.22 (m, 7H).

B. Exemplary Synthetic Schemes for Exemplary Androgen Receptor BindingMoiety Based Compounds

Exemplary Synthetic Scheme for Exemplary Compound 32

1. Synthesis of 5-bromo-3-methoxybenzene-1,2-dicarboxylic Acid

Into a 100-mL round-bottom flask, was placed4-bromo-2-methoxy-6-methylbenzonitrile (800 mg, 3.54 mmol, 1.00 equiv),water (10 mL), sodium hydroxide (708 mg, 17.70 mmol, 5.00 equiv), KMnO₄(1.12 g, 7.09 mmol, 2.00 equiv). The resulting solution was stirred for16 h at 100° C. in an oil bath. The solids were filtered out. The pHvalue of the solution was adjusted to 3 with hydrogen chloride (2mol/L). The resulting solution was extracted with dichloromethane (15mL×3) and the aqueous layers combined. The resulting solution wasextracted with ethyl acetate/methanol=10:1 (15 mL×3) and the organiclayers combined and dried in an oven under reduced pressure,concentrated under vacuum. This resulted in 330 mg (34%) of5-bromo-3-methoxybenzene-1,2-dicarboxylic acid as a white solid.

2. Synthesis of 1,2-dimethyl 5-bromo-3-methoxybenzene-1,2-dicarboxylate

Into a 100-mL round-bottom flask, was placed5-bromo-3-methoxybenzene-1,2-dicarboxylic acid (330 mg, 1.20 mmol, 1.00equiv), methanol (20 mL), sulfuric acid (5 mL). The resulting solutionwas stirred for 16 h at 70° C. in an oil bath. The resulting solutionwas diluted with water (40 mL). The pH value of the solution wasadjusted to 8 with sodium carbonate. The resulting solution wasextracted with ethyl acetate (30 mL×3) and the organic layers combinedand dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 340 mg (93%) of1,2-dimethyl 5-bromo-3-methoxybenzene-1,2-dicarboxylate as a whitesolid.

LC-MS (ES+): m/z 302.85 [MH+], t_(R)=0.906 min (2.0 minute run).

3. Synthesis of1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate

Into a 100-mL round-bottom flask, was placed 1,2-dimethyl5-bromo-3-methoxybenzene-1,2-dicarboxylate (300 mg, 0.99 mmol, 1.00equiv), tert-butyl piperazine-1-carboxylate (277 mg, 1.49 mmol, 1.50equiv), RuphosPd (39 mg, 0.05 mmol, 0.05 equiv), Cs₂CO₃ (978 mg, 3.00mmol, 3.00 equiv), toluene (15 mL). The resulting solution was stirredfor 12 h at 100° C. in an oil bath. The resulting solution was dilutedwith water (30 mL). The resulting solution was extracted with ethylacetate (30 mL×3) and the organic layers combined and dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with dichloromethane/ethyl acetate(10:1). This resulted in 340 mg (84%) of 1,2-dimethyl5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylateas light yellow oil.

LC-MS (ES+): m/z 409.05 [MH+], t_(R)=0.963 min (2.0 minute run).

4. Synthesis of5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylicacid

Into a 100-mL round-bottom flask, was placed 1,2-dimethyl5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate(340 mg, 0.83 mmol, 1.00 equiv), methanol/H₂O/THF (8 mL), sodiumol (100mg, 2.50 mmol, 3.00 equiv). The resulting solution was stirred for 12 hat 25° C. The resulting solution was diluted with water (30 mL). The pHvalue of the solution was adjusted to 8 with hydrogen chloride (2mol/L). citric acid monohydrate was employed to adjust the pH to 3. Theresulting solution was extracted with ethyl acetate (30 mL×3) and theorganic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 300 mg (95%) of5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylicacid as colorless oil.

LC-MS (ES+): m/z 306.95 [MH+], t_(R)=0.853 min (2.0 minute run).

5. Synthesis oftert-butyl-4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate

Into a 100-mL round-bottom flask, was placed tert-butyl4-(7-methoxy-1,3-dioxo-1,3-dihydro-2-benzofuran-5-yl)piperazine-1-carboxylate(260 mg, 0.72 mmol, 1.00 equiv), 3-aminopiperidine-2,6-dionehydrochloride (153.6 mg, 0.93 mmol, 1.30 equiv), pyridine (10 mL). Theresulting solution was stirred for 4 h at 120° C. in an oil bath. Theresulting solution was diluted with water (30 mL). The resultingsolution was extracted with ethyl acetate (30 mL×3) and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (100:1). This resulted in 280 mg (83%) oftert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylateas a yellow solid.

LC-MS (ES+): m/z 417.05 [MH+], t_(R)=0.852 min (2.0 minute run).

6. Synthesis of2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)isoindoline-1,3-dione

Into a 50-mL round-bottom flask, was placed tert-butyl4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate(270 mg, 0.57 mmol, 1 equiv), dichloromethane (6 mL, 0.07 mmol, 0.124equiv), TFA (2 mL, 0.02 mmol, 0.031 equiv). The resulting solution wasstirred for 2 hr at 25° C. The resulting mixture was concentrated togive2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)isoindoline-1,3-dioneas a brown oil.

LC-MS (ES+): m/z 373.05 [MH+], t_(R)=0.155 min (2.0 minute run).

7. Synthesis of6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide

Into a 100-mL round-bottom flask, was placed2,2,2-trifluoroacetaldehyde;2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione(130 mg, 0.28 mmol, 1.078 equiv), dichloromethane (10 mL, 0.12 mmol),6-(4-formylpiperidin-1-yl)-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide(120 mg, 0.26 mmol, 1 equiv), NaBH(OAc)₃ (163.4 mg, 0.77 mmol, 3.006equiv). The resulting solution was stirred for 2 hr at 25° C. Theresulting solution was diluted with dichloromethane (30 mL). Theresulting mixture was washed with H₂O (30 mL×3). The mixture was driedover anhydrous sodium sulfate and concentrated under vacuum. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/ethyl acetate (3:1). Thecrude product was purified by Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,Water (10 mmol/L NH₄HCO₃) and acetonitrile (43% Phase B up to 65% in 8min); Detector, uv. This resulted in 70 mg (33.11%) of6-[4-[4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamideas a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.57 (d, J=8.4 Hz, 1H),7.87-7.79 (m, 2H), 7.39-7.32 (m, 2H), 7.15-7.12 (m, 1H), 6.96 (s, 1H),6.68 (s, 1H), 5.04-4.98 (m, 1H), 4.50-4.47 (m, 3H), 4.93-3.85 (m, 4H),3.35-3.33 (m, 5H), 3.07-2.81 (m, 3H), 2.51 (s, 3H), 2.27-22.1 (m, 2H),2.09-2.01 (m, 2H), 2.00-1.49 (m, 11H), 1.23-1.11 (m, 3H); LC-MS (ES+):m/z 824.25/826.25 [MH+], t_(R)=182 min (3.0 minute run).

Chemical Formula: C₄₂H₄₆ClN₉O₇ [823.32/825.32]

Total H count from HNMR data: 46.

Exemplary Synthesis of Exemplary Compound 34

rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2′-(2,6-dioxopiperidin-3-yl)-3′-oxospiro[cyclopropane-1,1′-isoindolin]-6′-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide

Step 1: Synthesis of dimethyl 2-bromopentanedioate

To a solution of glutaric acid (30 g, 227.07 mmol, 1 eq) in chloroform(90 mL) was added thionyl chloride (59 g, 499.56 mmol, 36 mL, 2.2 eq).The mixture was stirred at 70° C. for 1 h. Liquid bromine (36.29 g,227.07 mmol, 1 eq) was added into the mixture dropwise. The mixture wasstirred at 70° C. for 12 h. The mixture was cooled to 0° C. and methanol(58 g, 1.82 mol, 73 mL, 8 eq) was added into the mixture drop wise at 0°C. LCMS detected the desired product. The mixture was extracted withethyl acetate (150 mL×3) and washed with saturated aqueous sodiumbicarbonate (200 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was purified with Flash C18 columnchromatography (acetonitrile:water=1:0 to 1:1). Dimethyl2-bromopentanedioate (4g+20 g (crude), 16.73 mmol, 7% yield) wasobtained as a yellow oil.

LCMS: MS (ESI) m/z: 241.0 [M+1]⁺.

Chemical Formula: C₇H₁₁BrO₄, Molecular Weight: 239.06

¹H NMR: (400 MHz, DCCl₃) δ: 4.39-4.36 (m, 1H), 3.78 (s, 3H), 3.72 (s,3H), 2.56-2.49 (m, 2H), 2.44-2.34 (m, 1H), 2.33-2.23 (m, 1H).

Total H count from HNMR data: 11.

Step 2: Synthesis of tert-butyl4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

To a solution of methyl 2-cyano-4-fluoro-benzoate (10 g, 55.82 mmol, 1eq), tert-butyl piperazine-1-carboxylate (12.48 g, 66.98 mmol, 1.2 eq)in dimethylsulfoxide (100 mL) was added diisopropylethylamine (28.86 g,223.28 mmol, 4 eq). The reaction mixture was stirred at 120° C. for 12h. Thin layer chromatography (petroleum ether: Ethyl acetate=3:1) showedmethyl 2-cyano-4-fluoro-benzoate was consumed, and desired product wasdetected. The mixture was poured into water (50 mL), and filtered. Thefiltrate was dried under vacuum. The residue was purified with silicagel column chromatography (petroleum ether:ethyl acetate=10:1 to 3:1).Tert-butyl 4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate(18 g, 52.11 mmol, 93% yield) was obtained as a yellow solid.

Chemical Formula: C₁₈H₂₃N₃O₄, Molecular Weight: 345.39

Step 3: Synthesis of tert-butyl4-(1′-oxospiro[cyclopropane-1,3′-isoindoline]-5′-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate (18 g,52.11 mmol, 1 eq) in tetrahydrofuran (200 mL) was added tetraisopropyltitanate (17.77 g, 62.54 mmol, 1.2 eq) and a solution of ethyl magnesiumbromide in tetrahydrofuran (2 M, 52.11 mL, 2 eq) at 0° C. The mixturewas stirred at 25° C. for 1 h. Thin layer chromatography (petroleumether:ethyl acetate=1:1) showed tert-butyl 4-(3-cyano-4-methoxycarbony1-phenyl)piperazine-1-carboxylate was consumed, and desired product wasdetected. The mixture was added into saturated aqueous ammonium chloride(150 mL). The mixture was extracted with ethyl acetate (100 mL×3). Theorganic layer was dried over sodium sulfate and concentrated. Theresidue was triturated with ethyl acetate (30 mL) and filtered.Tert-butyl4-(1′-oxospiro[cyclopropane-1,3′-isoindoline]-5′-yl)piperazine-1-carboxylate(6 g, 17.47 mmol, 33% yield) was obtained as a yellow solid.

Chemical Formula: C₁₉H₂₅O₃N₃, Molecular Weight: 343.42

¹H NMR: (400 MHz, CDCl₃) δ: 7.75-7.73 (d, J=8.8 Hz, 1H), 6.97-6.95 (d,J=8.8 Hz, 1H), 6.94-6.85 (m, 1H), 6.41 (s, 1H), 3.61-3.58 (t, J=4.8 Hz,4H), 3.28-3.25 (t, J=4.8 Hz, 4H), 1.56 (s, 2H), 1.49 (s, 9H), 1.38-1.36(m, 2H).

Total H count from HNMR data: 25.

Step 4: Synthesis of dimethyl2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]pentanedioate

20 batches in parallel:

To a solution of tert-butyl4-(1′-oxospiro[cyclopropane-1,3′-isoindoline]-5′-yl)piperazine-1-carboxylate(100 mg, 0.29 mmol, 1 eq) and dimethyl 2-bromopentanedioate (104 mg,0.44 mmol, 1.5 eq) in dimethylformamide (2 mL) was added sodium hydride(35 mg, 0.88 mmol, 60% in mineral oil, 3 eq). The mixture was stirred at30° C. for 12 h. Thin layer chromatography (petroleum ether:ethylacetate=1:1) showed 30% of the tert-butyl4-(1′-oxospiro[cyclopropane-1,3′-isoindoline]-5′-yl)piperazine-1-carboxylatewas consumed. The 20 reaction mixtures were poured into 50 mL of brine,and extracted with ethyl acetate (30 mL×2), the combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated invacuum. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=3/1 to 1/1). Dimethyl2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]pentanedioate(200 mg, 0.40 mmol, 10% yield corrected for recovered starting material)was obtained as a yellow oil. Also isolated was tert-butyl4-(1′-oxospiro[cyclopropane-1,3′-isoindoline]-5′-yl)piperazine-1-carboxylate(675 mg).

Chemical Formula: C₂₆H₃₅N₃O₇, Molecular Weight: 501.57

Step 5: Synthesis of2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]pentanedioicAcid

To a solution of dimethyl2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]pentanedioate(800 mg, 1.59 mmol, 1 eq) in tetrahydrofuran (5 mL) and methanol (5 mL)was added a solution of sodium hydroxide (255 mg, 6.38 mmol, 4 eq) inwater (3 mL). The mixture was stirred at 25° C. for 2 hr. LCMS showedthe reaction was completed and desired MS was detected. The mixturetogether with the other batch was poured into 20 mL water, and adjustedthe pH to 3.0 with 2.0 N hydrochloride acid, then extracted with ethylacetate (30 mL×3). The combined organic layers were dried over anhydroussodium sulfate, then concentrated in vacuum.2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]pentanedioicacid (740 mg, 1.56 mmol, 97% yield) as an off-white solid was obtained,which was directly used for the next step without further purification.

LCMS: MS (ESI) m/z: 474.3[M+1]⁺.

Chemical Formula: C₂₄H₃₁N₃O₇, Molecular Weight: 473.52

Step 6: Synthesis of5-amino-4-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]-5-oxo-pentanoicacid;5-amino-2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]-5-oxo-pentanoicacid and tert-butyl4-[2′-(2,6-dioxo-3-piperidyl)-1′-oxo-spiro[cyclopropane-1,3′-isoindoline]-5′-yl]piperazine-1-carboxylate

A mixture of2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]pentanedioicacid (400 mg, 0.85 mmol, 1 eq) and urea (253 mg, 4.22 mmol, 5 eq) in1-methyl-2-pyrrolidinone (4 mL) was heated to 160° C. and stirred at160° C. for 2 hours. LCMS showed two peaks with desired MS signals. Themixture together with the other batch was filtered. The filtrate wasfurther purified by Semi-preparative reverse phase HPLC (column: BostonGreen ODS 150*30 5 um; mobile phase: [water (0.225% formicacid)-acetonitrile]; B %: 35%-45%, 10 min). 2 isomeric mono-amides5-amino-4-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]-5-oxo-pentanoicacid and5-amino-2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]-5-oxo-pentanoicacid were obtained (170 mg, 0.36 mmol, 42% yield and 90 mg, 0.19 mmol,22% yield respectively. It was not conclusively established which of the2 isomeres corresponds to which structure.) Also isolated was tert-butyl4-[2′-(2,6-dioxo-3-piperidyl)-1′-oxo-spiro[cyclopropane-1,3′-isoindoline]-5′-yl]piperazine-1-carboxylate (90 mg, 0.20 mmol, 23%yield) as an off-white solid.

LCMS: mono-amide product 1: MS (ESI) m/z: 473.1[M+1]⁺, Mono-amideproduct 2: MS (ESI) m/z: 473.1[M+1]⁺, Imide product 3: MS (ESI) m/z:455.1[M+1]⁺.

Chemical Formula mono-amide product 1: C₂₄H₃₂N₄O₆, Molecular Weight:472.53.

Chemical Formula mono-amide product 2: C₂₄H₃₂N₄O₆, Molecular Weight:472.53.

Chemical Formula Imide product: C₂₄H₃₀N₄O₅, Molecular Weight: 454.52.

Step 7a: Synthesis of 3-(3′-oxo-6′-piperazin-1-yl-spiro[cyclopropane-1,1′-isoindoline]-2′-yl)piperidine-2,6-dione from the mono-amideproduct 1 of step 6

To a mixture of5-amino-2-[6′-(4-tert-butoxycarbonylpiperazin-1-yl)-3′-oxo-spiro[cyclopropane-1,1′-isoindoline]-2′-yl]-5-oxo-pentanoicacid (190 mg, 0.40 mmol, 1 eq, the first eluting mono-amide product fromabove) in acetonitrile (15 mL) was added benzenesulfonic acid (114 mg,0.72 mmol, 1.80 eq) in one portion at 25° C. under nitrogen atmosphere.The mixture was stirred at 90° C. for 3 hours. LCMS showed the productwas the main peak. The mixture was concentrated in vacuum. The residuewas purified by Semi-preparative reverse phase HPLC (column: BostonGreen ODS 150*30 5 um; mobile phase: [water (0.225% formicacid)-acetonitrile]; B %: 1%-27%, 10 min). The product3-(3′-oxo-6′-piperazin-1-yl-spiro[cyclopropane-1,1′-isoindoline]-2′-yl)piperidine-2,6-dione(55 mg, 0.14 mmol, 34% yield, benzene sulfonate) was obtained as a brownsolid.

LCMS: EW4875-628-P1B, MS (ESI) m/z: 355.1[M+1]⁺.

Chemical Formula: C₁₉H₂₂N₄O₃, Molecular Weight: 354.40.

Step 7b: Synthesis of 3-(3′-oxo-6′-piperazin-1-yl-spiro[cyclopropane-1,1′-isoindoline]-2′-yl)piperidine-2,6-dione from the Imide Product ofStep 6

To a mixture of tert-butyl4-[2′-(2,6-dioxo-3-piperidyl)-1′-oxo-spiro[cyclopropane-1,3′-isoindoline]-5′-yl]piperazine-1-carboxylate (90 mg, 0.20 mmol, 1eq) in dichloromethane (5 mL) was added hydrochloric acid (4 M indioxane, 2.5 mL, 50 eq) in one portion at 25° C. The mixture was stirredat 25° C. for 1 hour. LCMS showed the product was the main peak. Themixture was concentrated in vacuum. The crude solid The product3-(3′-oxo-6′-piperazin-1-yl-spiro[cyclopropane-1,1′-isoindoline]-2′-yl)piperidine-2,6-dione(70 mg, 0.18 mmol, 90% yield, hydrochloride) was obtained as a brownsolid, which was directly used into the next step without furtherpurification.

LCMS: MS (ESI) m/z: 355.1[M+1]⁺.

Chemical Formula: C₁₉H₂₂N₄O₃, Molecular Weight: 354.40

Step 8: Synthesis ofN-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-[[4-[2′-(2,6-dioxo-3-piperidyl)-1′-oxo-spiro[cyclopropane-1,3′-isoindoline]-5′-yl]piperazin-1-yl]methyl]-1-piperidyl]benzamide

To a solution ofN-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-formyl-1-piperidyl)benzamide(63 mg, 0.12 mmol, 1 eq) in 1,2-dichloroethane (3 mL) was addedtriethylamine (38 mg, 0.38 mmol, 3 eq) and3-(3′-oxo-6′-piperazin-1-yl-spiro[cyclopropane-1,1′-isoindoline]-2′-yl)piperidine-2,6-dione(50 mg, 0.12 mmol, 1 eq, hydrochloride). The mixture was stirred at 30°C. for 30 min. Sodium triacetoxyborohydride (54 mg, 0.25 mmol, 2 eq) wasadded, then the mixture was stirred at 30° C. for 12 hours. LCMS showedthe reaction was completed and desired MS can be detected. The reactionmixture was concentrated under reduced pressure to remove solution. Theresidue was purified by Semi-preparative reverse phase HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B %: 40%-70%, 10 min) to giveN-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-[[4-[2′-(2,6-dioxo-3-piperidyl)-1′-oxo-spiro[cyclopropane-1,3′-isoindoline]-5′-yl]piperazin-1-yl]methyl]-1-piperidyl]benzamide(17.8 mg, 0.02 mmol, 16% yield, 98% purity) as a white solid.

LCMS: MS (ESI) m/z: 932.3 [M+1]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ: 10.88 (s, 1H), 8.22 (s, 1H), 7.91 (d,J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.53-7.45 (m, 2H), 7.21 (d, J=2.4Hz, 1H), 6.99 (dd, J=9.2, 17.6 Hz, 4H), 6.73 (s, 1H), 4.33 (s, 1H), 4.06(d, J=9.2 Hz, 1H), 3.86 (d, J=12.4 Hz, 3H), 3.32-3.29 (m, 9H), 2.80 (t,J=12.0 Hz, 3H), 2.59-2.54 (m, 4H), 2.22 (d, J=6.8 Hz, 2H), 1.81 (d,J=10.3 Hz, 4H), 1.55-1.47 (m, 2H), 1.45-1.31 (m, 2H), 1.25-1.17 (s, 8H),1.13 (s, 6H).

Chemical Formula: C₄₇H₅₄ClN₇O₅, Molecular Weight: 832.43.

Total H count from HNMR data: 54.

C. Exemplary Synthetic Schemes for Exemplary Androgen Receptor BindingMoiety Based Compounds that are Imide Isosteres General Synthetic SchemeC-1 Synthesis of building blockN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide

Step 1: Synthesis of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinicAcid

6-Chloronicotinic acid (1.6 g, 10.0 mmol) was dissolved inN,N-dimethylacetamide (15 mL), and tert-butyl piperazine-1-carboxylate(1.9 g, 10.0 mmol) and ethyldiisopropylamine (2.6 g, 20 mmol) were addedthereto, followed by stirring at 130° C. overnight. The reaction mixturewas concentrated under reduced pressure, and to the obtained residue wasadded a 1 M aqueous NaOH solution (10 mL), followed by washing withCHCl₃ (50 mL). The pH of the aqueous layer was adjusted to around 6 to 7by the addition of 1 M hydrochloric acid, followed by extraction withCHCl₃ (50 mL×3). The organic layer was dried over anhydrous sodiumsulfate and the solvent was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CH₂C12/MeOH=10/1) to give6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g, 65%yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min). Purity is 83.17%, Rt=1.312min. MS Calcd.: 307.15; MS Found: 308.2 [M+H]⁺.

Chemical Formula: C₁₅H₂₁N₃O₄, Molecular Weight: 307.34.

Step 2: Synthesis of tert-butyl4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid(614 mg, 2.0 mmol),4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrilehydrochloride (630 mg, 2.0 mmol),2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (1.1 g, 3.0 mmol) and ethyldiisopropylamine (516 mg,4.0 mmol) in dichloromethane (20 mL) was stirred at room temperatureovernight. Water (50 mL) was added and extracted with dichloromethane(50 mL×3). Combined organic layers were washed by brine (50 mL×2), driedover anhydrous sodium sulfate. The solvent was concentrated to give theresidue, which was purified by column chromatography on silica gel(petroleum ether/ethyl acetate=1/1) to give tert-butyl4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate(977 mg, 86% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min). Purity is 88.26%, Rt=2.161min. MS Calcd.: 567.26; MS Found: 568.3 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (6H, s), 1.22 (6H, s), 1.43 (9H, s),3.42-3.44 (4H, m), 3.60-3.63 (4H, m), 4.02-4.07 (1H, m), 4.31 (1H, s),6.88 (1H, d, J=8.8 Hz), 7.00 (1H, dd, J=8.4, 2.4 Hz), 7.21 (1H, d, J=2.4Hz), 7.65 (1H, d, J=9.2 Hz), 7.91 (1H, d, J=8.8 Hz), 7.99 (1H, dd,J=8.8, 2.4 Hz), 8.64 (1H, d, J=2.4 Hz).

Chemical Formula: C₃₀H₃₈ClN₅O₄, Molecular Weight: 568.11.

Total H count from HNMR data: 38.

Step 3: Synthesis ofN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamideHydrochloride

A mixture of tert-butyl4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate (405 mg, 0.7 mmol) inHCl/1,4-dioxane (10 mL) was stirred at room temperature for 4 h. Thesolvent was removed in vacuum to giveN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamidehydrochloride (353 mg, 100% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min). Rt=1.791 min. MS Calcd.:467.21; MS Found: 468.3 [M+H]⁺.

Chemical Formula: C₂₅H₃₁Cl₂N₅O₂, Molecular Weight: 504.45

General Synthetic Scheme C-2 Synthesis of Building Block tert-butyl4-(4-formylpiperidin-1-yl)benzoate

Step 1: Synthesis of tert-butyl4-(4-(hydroxymethyl)piperidin-1-yl)benzoate

To a solution of tert-butyl 4-fluorobenzoate (23 g, 0.12 mmol) in DMSO(100 mL) was added piperidin-4-ylmethanol (40.5 g, 0.35 mmol). Themixture was heated to 120° C. overnight under nitrogen. After cooling toroom temperature, water (50 mL) was added to the reaction mixture, andextracted with ethyl acetate (20 mL×3). The organic layer was washedwith brine (15 mL×3). The combined organic phases were dried overanhydrous sodium sulfate and concentrated in vacuo, and purified by CC(PE/EA=10:1) to give compound tert-butyl4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (31 g, 91.2%) as a whitesolid.

LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100 (v/v)] and 10%[(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] to 10% [(total 10 mMAcONH₄) water/CH₃CN=900/100 (v/v)] and 90% [(total 10 mM AcONH₄)water/CH₃CN=100/900 (v/v)] in 1.6 min, then under this condition for 2.4min, finally changed to 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100(v/v)] and 10% [(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] in 0.1min and under this condition for 0.7 min). Purity is 99.57%, Rt=2.035min.; MS Calcd.: 291.2; MS Found: 292.2 [M+H]⁺.

HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm×4.6 mm×3.5μm); Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 5 min). Purity is 93.27%, Rt=9.542 min.

¹H NMR (400 MHz, CDCl₃) δ 1.29-1.40 (2H, m), 1.49 (1H, d, J=5.4 Hz),1.57 (9H, s), 1.70-1.75 (1H, m), 1.82 (2H, d, J=12.8 Hz), 2.80-2.87 (2H,m), 3.53 (2H, t, J=5.8 Hz), 3.87-3.90 (2H, m), 6.85 (2H, d, J=9.2 Hz),7.84 (2H, d, J=9.2 Hz).

Chemical Formula: C₁₇H₂₅NO₃, Molecular Weight: 291.39.

Total H count from HNMR data: 25.

Step 2: Synthesis of tert-butyl 4-(4-formylpiperidin-1-yl)benzoate

To a solution of tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate(300 mg, 1.03 mmol) in dichloromethane (20 mL) was added Dess-Martinperiodinane (1.31 g, 3.09 mmol) slowly at 0° C. The reaction mixture wasstirred at room temperature for 1 h. Then filtered, and concentrated invacuo to give compound tert-butyl 4-(4-formylpiperidin-1-yl)benzoate(240 mg, 81%) as a pale yellow solid.

Exemplary Synthesis of Exemplary Compound 46

N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide

Step 1: Synthesis of methyl 2-bromo-4-methoxybenzoate

To a solution of 2-bromo-4-methoxybenzoic acid (5.0 g, 21.7 mmol) inmethanol (50 mL) was added 98% sulfuric acid (0.5 ml). The reactionmixture was heated to 90° C. for 16 h under nitrogen gas, andconcentration under reduced pressure. After cooling to room temperature,sodium bicarbonate (2.0 M) was added to adjust PH=8. Thus was extractedwith ethyl acetate (50 mL×3). The organic layer was washed with brine(30 mL). The combined organic phases were dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give2-bromo-4-methoxybenzoate (4.8 g, 91%) as yellow oil.

Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6 mm×3.5μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100 (v/v)] and 10%[(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] to 10% [(total 10 mMAcONH₄) water/CH₃CN=900/100 (v/v)] and 90% [(total 10 mM AcONH₄)water/CH₃CN=100/900 (v/v)] in 1.6 min, then under this condition for 2.4min, finally changed to 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100(v/v)] and 10% [(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] in 0.1min and under this condition for 0.7 min. Purity is 98.94%, Rt=2.609min. MS Calcd.: 243.97; MS Found: 245.0 [M+H]⁺.

Step 2: Synthesis of methyl 2-allyl-4-methoxybenzoate

To a solution of methyl 2-bromo-4-methoxybenzoate (3.0 g, 12.3 mmol),cesium carbonate (12.0 g, 36.9 mmol),2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.98 g, 18.5 mmol) inN,N-dimethylformamide/water (30.0 mL/3.0 mL) was addedtetrakis(triphenylphosphine)palladium (1.42 g, 1.23 mmol) under nitrogenatmosphere. The reaction mixture was heated to 100° C. and stirred for 4h. The resulting reaction was concentrated under reduced pressure, andthen water (10 mL) was added. The mixture was extracted with ethylacetate (50 mL×3). The combined organic phase was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated.The residue was purified by silica gel chromatography column(petroether/ethyl acetate=4:1) to give the methyl2-allyl-4-methoxybenzoate (2.6 g, 100%) as yellow oil.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm×4.6 mm×3.5μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05 TFA] in 1.5 min, then under this condition for0.5 min, finally changed to 95% [water+0.05% TFA] and 5% [CH₃CN+0.05%TFA] in 0.1 min and under this condition for 0.5 min. Purity is 96.85%,Rt=1.293 min. MS Calcd.: 206.09; MS Found: 207.3 [M+H]⁺.

Step 3: Synthesis of methyl 4-methoxy-2-(2-oxoethyl)benzoate

To a solution of methyl 2-allyl-4-methoxybenzoate (1.20 g, 5.83 mmol)and osmium tetraoxide (5 mg) in acetonitrile, acetone, and water(v:v:v=10 mL:10 mL:10 mL) was added sodium periodate (4.99 g, 23.3 mmol)at 0° C. The mixture was stirred at room temperature for 4 h. Themixture was filtered through a pad of celite and extracted with ethylacetate (20×3 mL). The organic layer was separated, washed with waterand brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by prep-TLC (petroether/ethylacetate=4:1) to give compound methyl 4-methoxy-2-(2-oxoethyl)benzoate(420 mg, 35%) as yellow oil.

LC-MS (Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0%[water+0.05% TFA] and 100% [CH₃CN+0.05% TFA] in 1.5 min, then under thiscondition for 0.5 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.1 min and under this condition for 0.5 min.).Purity is 96.26%, Rt=1.007 min. MS Calcd.: 208.1; MS Found: 209.3[M+H]⁺.

Step 4: Synthesis of3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione

To a solution of methyl 4-methoxy-2-(2-oxoethyl)benzoate (420 mg, 2.02mmol) in methanol (6 mL) was added a solution of3-aminopiperidine-2,6-dione hydrochloride (397 mg, 2.42 mmol) andtriethylamine (245 mg, 2.24 mmol) in methanol (2 mL). The reactionmixture was stirred at room temperature for 1 h, then sodiumcyanoborohydride (254 mg, 4.04 mmol) was added at 0° C. The reaction wasstirred at room temperature overnight, water (10 mL) was added, andextracted with ethyl acetate (20 mL×3), washed with water and brine,dried over anhydrous sodium sulfate, filtered, and concentrated. Theresidue was purified by prep-TLC (dichloromethane/methanol=20:1) to give3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione(340 mg, 59%) as a pale yellow solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×3mm×2.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] to 5%[water+10 mM NH₄HCO₃] and 95% [CH₃CN+10 mM NH₄HCO₃] in 1.5 min, thenunder this condition for 0.5 min, finally changed to 95% [water+10 mMNH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] in 0.1 min and under thiscondition for 0.5 min.). Purity is 80.84%, Rt=0.924 min. MS Calcd.:288.1; MS Found: 289.1 [M+H]⁺.

Step 5: Synthesis of3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione

To a solution of3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione(220 mg, 0.76 mmol) in dichloromethane (10 mL) was added borontribromide (0.5 mL) in dichloromethane (2 mL) dropwise at −78° C. andstirred overnight at room temperature. The reaction mixture was added towater (10 mL) and sodium bicarbonate (20 mL), then extracted withdichloromethane/methanol (30 mL×5). The organic layer was washed withbrine (10 mL). The combined organic phases were dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by prep-TLC (dichloromethane/methanol=10:1) to give compound3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione(80 mg, 38%) as a yellow solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×3mm×2.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] to 5%[water+10 mM NH₄HCO₃] and 95% [CH₃CN+10 mM NH₄HCO₃] in 1.5 min, thenunder this condition for 0.5 min, finally changed to 95% [water+10 mMNH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] in 0.1 min and under thiscondition for 0.5 min.). Purity is 96.22%, Rt=0.736 min. MS Calcd.:274.1; MS Found: 275.1 [M+H]⁺.

Step 6: Synthesis of3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione

To a solution of3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione(80 mg, 0.292 mmol) in N,N-dimethylformamide (5.0 mL) was added5-chloropentyl 4-methylbenzenesulfonate (64.5 mg, 0.234 mmol) andpotassium carbonate (121 mg, 0.876 mmol). The mixture was heated to 40°C. overnight. After cooling to rt., the reaction mixture was added towater (10 mL), and extracted with ethyl acetate (20 mL×3). The organiclayer was washed with brine (10 mL×3). The combined organic phases weredried over anhydrous sodium sulfate, filtered, and concentrated invacuo. The residue was purified by prep-TLC(dichloromethane/methanol=10:1) to give3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione(25 mg, 23%) as a yellow solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×3mm×2.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] to 5%[water+10 mM NH₄HCO₃] and 95% [CH₃CN+10 mM NH₄HCO₃] in 1.5 min, thenunder this condition for 0.5 min, finally changed to 95% [water+10 mMNH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] in 0.1 min and under thiscondition for 0.5 min.). Purity is 93.68%, Rt=1.263 min. MS Calcd.:378.1; MS Found: 379.1 [M+H]⁺.

Step 7: Synthesis ofN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide

A solution of3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione(25 mg, 0.066 mmol) was dissolved in acetonitrile (2 mL),N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide(31 mg, 0.066 mmol), ethyldiisopropylamine (17 mg, 0.132 mmol),potassium iodide (2 mg) was added to the solution. The mixture washeated to 100° C. for 16 h under sealed tube. After cooling to rt., thereaction mixture was added to water (10 mL), and extracted with ethylacetate (10 mL×3). The organic layer was washed with brine (10 mL×3).The combined organic phases were dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo, then purified by prep-HPLC to givecompoundN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide(4.1 mg, 8%) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.). Purity is 87.84%, Rt=2.923min. MS Calcd.: 809.4; MS Found: 810.3 [M+H]⁺.

HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm×4.6 mm×3.5μm); Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 5 min). Purity is 84.56%, Rt=10.161min.

¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (6H, s), 1.21 (6H, s), 1.43-1.54 (4H,m), 1.74-1.78 (2H, m), 1.88-1.91 (1H, m), 2.30-2.44 (8H, m), 2.90-2.97(3H, m), 3.42-3.59 (7H, m), 4.03-4.07 (3H, m), 4.30 (1H, s), 6.86-6.91(3H, m), 6.99-7.02 (1H, m), 7.22 (1H, d, J=2.4 Hz), 7.64 (1H, d, J=8.8Hz), 7.79 (1H, d, J=8.8 Hz), 7.90-7.97 (2H, m), 8.62 (1H, d, J=2.0 Hz),10.90 (1H, s).

Chemical Formula: C₄₄H₅₂ClN₇O₆, Molecular Weight: 810.38.

Total H count from HNMR data: 52.

Exemplary Synthesis of Exemplary Compound 47

N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide

Step 1: Synthesis of 2-(carboxymethyl)-4-methoxybenzoic Acid

To a solution of 4-methoxy-2-methylbenzoic acid (5.0 g, 30.1 mmol) indry tetrahydrofuran (50 mL) was added lithium diisopropylamide intetrahydrofuran (1.0 mol/L)(66.3 mL, 66.3 mmol) at −78° C. undernitrogen gas. The mixture was left to stir for 1 hour at thattemperature and then dimethyl carbonate (2.98 g, 33.1 mmol) was added.The reaction mixture was left to stir overnight. Water (200 mL) andethyl acetate (100 mL) was added. The aqueous layer was separated,extracted with ethyl acetate (50 mL×2) and neutralized with hydrochloricacid (1 N) until pH<4. The mixture was extracted with ethyl acetate (100mL×2). The combined organic layers were washed with saturated brine(50.0 mL×2), dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was dissolved in dimethyl sulfoxide(40 mL) and lithium hydroxide hydrate (5.06 g, 120.4 mmol) was added.The mixture was stirred at 120° C. for 2 hour, cooled down to roomtemperature and poured into ice-water (200 mL). Hydrochloric acid (1 N)was added until pH<4. The mixture was extracted with ethyl acetate (100mL×2). The combined organic layers were washed with saturated brine(50.0 mL×2), dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give 2-(carboxymethyl)-4-methoxybenzoic acid(4.6 g, 73% two steps) as a yellow solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 95% [water+0.1% TFA] and 5% [CH₃CN+0.1% TFA] to 0%[water+0.1% TFA] and 100% [CH₃CN+0.1% TFA] in 0.5 min, then under thiscondition for 1.5 min, finally changed to 95% [water+0.1% TFA] and 5%[CH₃CN+0.1% TFA] in 0.1 min and under this condition for 0.5 min).Purity is 94.6%, Rt=0.774 min. MS Calcd.: 210.1; MS Found: 233.1[M+23]⁺.

Step 2: Synthesis of methyl 4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate

To a solution of (2-(carboxymethyl)-4-methoxybenzoic acid (1.2 g, 5.7mmol) in methanol (10.0 mL) was added thionyl chloride (1.7 g, 14.3mmol) dropwise. The mixture was refluxed for 2 hour. The mixture wascooled down to room temperature and then the solvent was removed invacuo to give crude product which was purified by column chromatographyon silica gel (ethyl acetate/petroleum ether=1:1) to give4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate (900 mg, 66%) as a whitesolid.

Step 3: Synthesis of 2-(carboxymethyl)-4-hydroxybenzoic Acid

To a solution of 4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate (0.9 g, 3.78mmol) in dichloromethane (30 mL) was added boron tribromide (4.7 g, 18.9mmol) dropwise under ice-water bath. The resulting mixture was allowedto warm to room temperature and stirred overnight. Water (100 mL) wasadded. The organic layer was separated, washed with brine (50 mL×2),dried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto give a mixture. The mixture was dissolved in methanol (30 mL) andsodium hydroxide (0.76 g, 18.9 mmol) in water (4.0 mL) was added. Themixture was refluxed for 5 hour. The solvent was removed. The residuewas dissolved in water (30 mL). Hydrochloric acid (1 N) was added untilpH<4. The mixture was extracted with ethyl acetate (50 mL×2). Thecombined organic layers were washed with saturated brine (20.0 mL×2),dried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto give 2-(carboxymethyl)-4-hydroxybenzoic acid (0.45 g, 61% two steps)as a yellow solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 95% [water+0.1% TFA] and 5% [CH₃CN+0.1% TFA] to 0%[water+0.1% TFA] and 100% [CH₃CN+0.1% TFA] in 0.5 min, then under thiscondition for 1.5 min, finally changed to 95% [water+0.1% TFA] and 5%[CH₃CN+0.1% TFA] in 0.1 min and under this condition for 0.5 min).Purity is 95.2%, Rt=0.570 min. MS Calcd.: 196.0; MS Found: 197.2 [M+H]⁺.

Step 4: Synthesis of2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic Acid

The mixture of 2-(carboxymethyl)-4-hydroxybenzoic acid (120 mg, 0.61mmol), potassium carbonate (253 mg, 1.83 mmol) and 5-chloropentyl4-methylbenzenesulfonate (506 mg, 1.83 mmol) in dimethyl sulfoxide (5mL) was stirred at 70° C. overnight. The resulting mixture was allowedto cooled down to room temperature and stirred overnight. Water (20 mL)and ethyl acetate (20 mL) was added. The organic layer was separated,washed with brine (50 mL×2), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give a mixture. The mixture wasdissolved in methanol (30 mL) and lithium hydroxide hydrate (128 mg,3.05 mmol) was added. The mixture was stirred at room temperatureovernight. The solvent was removed. The residue was dissolved in water(30 mL). Hydrochloric acid (1 N) was added until pH<4. The mixture wasextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with saturated brine (10 mL×2), dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic acid (85 mg,44% two steps) as yellow oil.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min.). Purity is 69.9%, Rt=0.829min. MS Calcd.: 314.1; MS Found: 315.1 [M+H]⁺.

Step 5: Synthesis of methyl4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate

To a solution of2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic acid (85 mg,0.27 mmol) in methanol (2 mL) was added thionyl chloride (48.3 mg, 0.41mmol) dropwise. The mixture was refluxed for 2 hour. The mixture wascooled down to room temperature and then the solvent was removed invacuo to give crude product which was purified by prep-TLC (ethylacetate/petroleum ether=1:1) to give methyl4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (55 mg, 62%) asyellow oil.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min.). Purity is 72.9%, Rt=1.208min. MS Calcd.: 328.1; MS Found: 329.2 [M+H]⁺.

Step 6: Synthesis of methyl4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate

The mixture of methyl4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (55 mg, 0.17mmol), ethyldiisopropylamine (65.8 mg, 0.51 mmol), potassium iodide(28.2 mg, 0.17 mmol) andN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide(78.5 mg, 0.17 mmol) in dimethyl sulfoxide (2 mL) was stirred at 70° C.overnight. The resulting mixture was allowed to cooled down to roomtemperature and stirred overnight. Water (20 mL) and ethyl acetate (20mL) was added. The organic layer was separated, washed with brine (50mL×2), dried over anhydrous sodium sulfate, filtered, and concentratedin vacuo to give the crude product which was purified by column andflash chromatography (ethyl acetate/petroleum ether=1:1) to give methyl4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate(53 mg, 41%) as a white solid.

Step 7: Synthesis of4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoicAcid

The mixture of methyl4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate(53 mg, 0.07 mmol) was dissolved in methanol (2 mL) and lithiumhydroxide hydrate (14.7 mg, 0.35 mmol) was added. The mixture wasstirred at room temperature for 3 hour. The solvent was removed. Theresidue was dissolved in water (15 mL). Hydrochloric acid (1 N) wasadded until pH<4. The mixture was extracted with ethyl acetate (15mL×2). The combined organic layers were washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, filtered, and concentratedin vacuo to give4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoicacid (42 mg, 81%) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min.). Purity is 75.4%, Rt=1.041min. MS Calcd.: 745.3; MS Found: 746.2 [M+H]⁺.

Step 8: Synthesis of methyl2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2,6-dioxopiperidin-3-ylcarbamoyl)phenyl)acetate

A solution of4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoicacid (42 mg, 0.056 mmol), HATU (25.5 mg, 0.067 mmol) andethyldiisopropylamine (29.7 mg, 0.23 mmol) in N, N-dimethylformamide (2mL) was stirred for 30 min, and then 3-aminopiperidine-2,6-dionehydrochloride (9.2 mg, 0.056 mmol) was added. The mixture was stirred atroom temperature overnight and water (10 mL) was added. The mixture wasextracted by ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (10 mL×3), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was purified byprep-TLC (dichloromethane/methanol=10:1) to give methyl2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2,6-dioxopiperidin-3-ylcarbamoyl)phenyl)acetate(45 mg, 94%) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min.). Purity is 77.7%, Rt=1.213min. MS Calcd.: 855.4; MS Found: 856.3 [M+H]⁺.

Step 9: Synthesis ofN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide

A solution of methyl2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2,6-dioxopiperidin-3-ylcarbamoyl)phenyl)acetate(45 mg, 0.053 mmol) in dimethyl sulfoxide (2 mL) was added sodiumhydroxide in water (2.5 moL/L, 2 drops). The mixture was stirred at roomtemperature for 5 min. Water (20 mL) and ethyl acetate (20 mL) wasadded. The organic layer was separated, washed with brine (10 mL×2),dried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto give the crude product which was purified by prep-HPLC to giveN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide(18.5 mg, 42%) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100 (v/v)] and 10%[(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] to 10% [(total 10 mMAcONH₄) water/CH₃CN=900/100 (v/v)] and 90% [(total 10 mM AcONH₄)water/CH₃CN=100/900 (v/v)] in 1.6 min, then under this condition for 2.4min, finally changed to 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100(v/v)] and 10% [(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] in 0.1min and under this condition for 0.7 min). Purity is 100.0%, Rt=2.988min. MS Calcd.: 823.4; MS Found: 824.3 [M+H]⁺.

HPLC (Agilent HPLC 1200; Column: L-column2 ODS (150 mm*4.6 mm*5.0 μm);Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase: from95% [water+0.1% TFA] and 5% [CH₃CN+0.1% TFA] to 0% [water+0.1% TFA] and100% [CH₃CN+0.1% TFA] in 10 min, then under this condition for 5 min,finally changed to 95% [water+0.1% TFA] and 5% [CH₃CN+0.1% TFA] in 0.1min and under this condition for 5 min). Purity is 95.2%, Rt=8.168 min.

¹H NMR (400 MHz, DMSO-d⁶) δ 1.12 (6H, s), 1.21 (6H, s), 1.37-1.58 (4H,m), 1.73-1.81 (2H, m), 1.86-1.91 (1H, m), 2.30-2.37 (2H, m), 2.40-2.46(2H, m), 2.82-2.91 (1H, m), 3.30-3.35 (4H, m), 3.55-3.65 (4H, m),4.03-4.30 (6H, m), 5.54-5.63 (1H, m), 6.87 (1H, d, J=9.6 Hz), 6.96-7.07(3H, m), 7.21 (1H, d, J=2.4 Hz), 7.63 (1H, d, J=9.6 Hz), 7.90-8.04 (3H,m), 8.62 (1H, d, J=2.4 Hz), 10.93 (1H, s).

Chemical Formula: C₄₄H₅₀ClN₇O₇, Molecular Weight: 824.36.

Total H count from HNMR data: 50.

Exemplary Synthesis of Exemplary Compound 48

N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)oxy)pentyl)piperazin-1-yl)nicotinamide

Step 1: Synthesis of 4-(5-(benzyloxy)pentyloxy)-2-chloropyridine

To a solution of 2-chloropyridin-4-ol (1.3 g, 10.0 mmol) in DMF (15 mL)was added sodium hydride (60% dispersed in mineral oil, 482 mg, 12.0mmol) at 0° C., and the mixture was stirred at room temperature for 30min. Then ((5-bromopentyloxy)methyl)benzene (3.1 g, 12.0 mmol) was addedto the reaction and the resulted mixture was stirred at 50° C.overnight. When the reaction was completed (monitored by TLC), water (30mL) was added. The resultant mixture was extracted by ethyl acetate (10mL×3) and the combined organic layers were washed by brine (20 mL×3),dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by column chromatography on silica (petroleum/ethylacetate=1/4) to give 4-(5-(benzyloxy)pentyloxy)-2-chloropyridine (2.4 g,78% yield) as a brown solid.

¹H NMR (400 MHz, CDCl₃) δ 1.47-1.53 (2H, m), 1.59-1.64 (2H, m),1.71-1.76 (2H, m), 3.42 (2H, t, J=6.4 Hz), 3.91 (2H, t, J=6.4 Hz), 4.44(2H, s), 7.07-7.15 (2H, m), 7.23-7.28 (5H, m), 7.96 (1H, d, J=3.2 Hz).

Step 2: Synthesis of 4-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine

To a microwave glass vial was added4-(5-(benzyloxy)pentyloxy)-2-chloropyridine (2.0 g, 6.5 mmol), hydrazinemonohydrate (10 mL) and EtOH (10 mL), and the mixture was stirred undermicrowave conditions at 120° C. for 8 h. When it was cooled to roomtemperature, water (20 mL) was added to the reaction. The resultantmixture was extracted by ethyl acetate (10 mL×3) and the combinedorganic layers were washed by brine (15 mL×3), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue (1.6 g,83% yield) was directly used to the next step without furtherpurification as brown oil.

Step 3: Synthesis of7-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

To a solution of 5-ethoxy-2-hydrazinylpyridine (1.6 g, 5.4 mmol) inacetonitrile (25 mL) was added CDI (1.3 g, 8.2 mmol), and the mixturewas stirred at 80° C. for 2 h. When it was cooled to room temperature,water (20 mL) was added to the reaction. The resultant mixture wasextracted by ethyl acetate (10 mL×3) and the combined organic layerswere washed by brine (15 mL×3), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was purified by columnchromatography on silica (DCM/MeOH=20/1) to give7-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (360mg, 20% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Purity is 96.77%, Rt=1.716min. MS Calcd.: 327.16; MS Found: 328.2 [M+H]⁺.

Step 4: Synthesis of3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione

The solution of7-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (300mg, 0.9 mmol), 3-bromopiperidine-2,6-dione (438 mg, 2.3 mmol) and K₂CO₃(253 mg, 1.8 mmol) in acetonitrile (10 mL) was stirred at 80° C.overnight. When it was cooled to room temperature, water (10 mL) wasadded. The resultant mixture was extracted by ethyl acetate (10 mL×3)and the combined organic layers were washed by brine (10 mL×3), driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by Prep-TLC (DCM/MeOH=20/1) to give3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(157 mg, 39% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Purity is 99.45%, Rt=1.836min. MS Calcd.: 438.19; MS Found: 439.3 [M+H]⁺.

Step 5: Synthesis of3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione

To a solution of3-(7-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(157 mg, 0.4 mmol) in CHCl₃ (5 mL) was added TMSI (143 mg, 0.7 mmol),and the mixture was stirred at room temperature overnight. Then themixture was washed by sat. NaHSO₃ (5 mL×2), washed by brine (5 mL×2),dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by Prep-TLC (DCM/MeOH=15/1) to give3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(130 mg, 79% yield) as a white solid.

LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Purity is 100%, Rt=1.754 min.MS Calcd.: 458.05; MS Found: 459.1 [M+H]⁺.

Step 6: Synthesis ofN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yloxy)pentyl)piperazin-1-yl)nicotinamide

A solution of3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(85 mg, 0.2 mmol),N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide(87 mg, 0.2 mmol), and ethyldiisopropylamine (72 mg, 0.6 mmol) inacetonitrile (5 mL) was stirred at 80° C. overnight. When it was cooledto room temperature, water (5 mL) was added and the mixture wasextracted by ethyl acetate (5 mL×3) and the combined organic layers werewashed by brine (5 mL×3), dried over anhydrous sodium sulfate, filteredand concentrated. The residue was purified by Prep-HPLC to giveN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yloxy)pentyl)piperazin-1-yl)nicotinamide(50 mg, 34% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Purity is 100%, Rt=2.877 min.MS Calcd.: 797.34; MS Found: 798.3 [M+H]⁺.

HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm×4.6 mm×3.5μm); Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 5 min.) Purity is 93.85%, Rt=9.967 min.

¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (6H, s), 1.21 (6H, s), 1.43-1.47 (2H,m), 1.49-1.53 (2H, m), 1.73-1.78 (2H, m), 2.13-2.17 (1H, m), 2.32 (2H,t, J=7.2 Hz), 2.43-2.47 (5H, m), 2.61-2.62 (1H, m), 2.87-2.93 (1H, m),3.59 (4H, s), 4.01-4.07 (3H, m), 4.30 (1H, s), 5.28 (1H, dd, J=12.4, 5.2Hz), 6.35 (1H, dd, J=8.0, 2.4 Hz), 6.52 (1H, d, J=1.6 Hz), 6.86 (1H, d,J=8.8 Hz), 7.00 (1H, dd, J=8.8, 2.4 Hz), 7.21 (1H, d, J=2.4 Hz), 7.63(1H, d, J=9.2 Hz), 7.80 (1H, d, J=8.0 Hz), 7.90 (1H, d, J=8.8 Hz), 7.95(1H, dd, J=9.2, 2.4 Hz), 8.62 (1H, d, J=2.4 Hz), 11.09 (1H, s).

Chemical Formula: C₄₁H₄₈ClN₉O₆, Molecular Weight: 798.33.

Total H count from HNMR data: 48.

Exemplary Synthesis of Exemplary Compound 49

N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide

Step 1: Synthesis of 5-(5-(benzyloxy)pentyloxy)-2-chloropyridine

To a solution of 6-chloropyridin-3-ol (1.0 g, 7.7 mmol) in DMF (10 mL)was added sodium hydride (60% dispersed in mineral oil, 371 mg, 9.3mmol) at 0° C., and the mixture was stirred at room temperature for 30min. Then ((5-bromopentyloxy)methyl)benzene (2.0 g, 7.7 mmol) was addedto the reaction and the resulted mixture was stirred at room temperaturefor 2 h. When the reaction was completed (monitored by TLC), water (30mL) was added. The resultant mixture was extracted by ethyl acetate (10mL×3) and the combined organic layers were washed by brine (10 mL×3),dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue (1.6 g, 68% yield) was directly used to the next step withoutfurther purification as a brown solid.

Step 2: Synthesis of 5-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine

To a microwave glass vial was added5-(5-(benzyloxy)pentyloxy)-2-chloropyridine (1.6 g, 5.2 mmol) andhydrazine monohydrate (20 mL), and the mixture was stirred undermicrowave conditions at 170° C. for 18 h. When it was cooled to roomtemperature, water (20 mL) was added to the reaction. The resultantmixture was extracted by ethyl acetate (10 mL×3) and the combinedorganic layers were washed by brine (15 mL×3), dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue (1.3 g,82% yield) was directly used to the next step without furtherpurification as brown oil.

Step 3: Synthesis of6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

To a solution of 5-(5-(benzyloxy)pentyloxy)-2-hydrazinylpyridine (1.3 g,4.4 mmol) in acetonitrile (30 mL) was added CDI (1.1 g, 6.7 mmol), andthe mixture was stirred at 80° C. for 2 h. When it was cooled to roomtemperature, water (20 mL) was added to the reaction. The resultantmixture was extracted by ethyl acetate (10 mL×3) and the combinedorganic layers were washed by brine (15 mL×3), dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica (DCM/MeOH=20/1) to give6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (280mg, 19% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Purity is 98.98%, Rt=1.728min. MS Calcd.: 327.16; MS Found: 328.1 [M+H]⁺.

Step 4: Synthesis of3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione

The solution of6-(5-(benzyloxy)pentyloxy)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (280mg, 0.9 mmol), 3-bromopiperidine-2,6-dione (438 mg, 2.3 mmol) and K₂CO₃(253 mg, 1.8 mmol) in acetonitrile (10 mL) was stirred at 80° C.overnight. When it was cooled to room temperature, water (10 mL) wasadded. The resultant mixture was extracted by ethyl acetate (10 mL×3)and the combined organic layers were washed by brine (10 mL×3), driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by Prep-TLC (DCM/MeOH=20/1) to give3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(155 mg, 41% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Purity is 85.76%, Rt=1.675min. MS Calcd.: 438.19; MS Found: 439.2 [M+H]⁺.

Step 5: Synthesis of3-(6-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione

To a solution of3-(6-(5-(benzyloxy)pentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(155 mg, 0.4 mmol) in CHCl₃ (5 mL) was added TMSI (143 mg, 0.7 mmol),and the mixture was stirred at room temperature overnight. Then themixture was washed by sat. NaHSO₃ (5 mL×2), washed by brine (5 mL×2),dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by Prep-TLC (DCM/MeOH=15/1) to give3-(7-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(130 mg, 79% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Purity is 95.44%, Rt=1.706min. MS Calcd.: 458.05; MS Found: 459.1 [M+H]⁺.

Step 6: Synthesis ofN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide

A solution of3-(6-(5-iodopentyloxy)-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(85 mg, 0.2 mmol),N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide(87 mg, 0.2 mmol), and ethyldiisopropylamine (72 mg, 0.6 mmol) inacetonitrile (5 mL) was stirred at 80° C. overnight. When it was cooledto room temperature, water (5 mL) was added and the mixture wasextracted by ethyl acetate (5 mL×3) and the combined organic layers werewashed by brine (5 mL×3), dried over anhydrous sodium sulfate, filtered,and concentrated. The residue was purified by Prep-HPLC to giveN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide(58 mg, 39% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min.) Purity is 100%, Rt=2.890 min.MS Calcd.: 797.34; MS Found: 798.3 [M+H]⁺.

HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm×4.6 mm×3.5μm); Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 5 min.) Purity is 93.46%, Rt=10.027min.

¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (6H, s), 1.21 (6H, s), 1.44-1.48 (2H,m), 1.52-1.58 (2H, m), 1.74-1.79 (2H, m), 2.15-2.19 (1H, m), 2.30 (2H,t, J=7.2 Hz), 2.43-2.50 (4H, m), 2.51-2.67 (2H, m), 2.86-2.95 (1H, m),3.60 (4H, s), 3.97 (2H, t, J=6.4 Hz), 4.05 (1H, d, J=9.2 Hz), 4.30 (1H,s), 5.38 (1H, dd, J=5.2, 12.8 Hz), 6.86 (1H, d, J=9.2 Hz), 7.00 (1H, dd,J=8.4, 2.4 Hz), 7.10 (1H, dd, J=10.0, 2.0 Hz), 7.21 (1H, d, J=2.4 Hz),7.25 (1H, d, J=10.0 Hz), 7.36 (1H, s), 7.62 (1H, d, J=9.2 Hz), 7.90 (1H,d, J=8.8 Hz), 7.95 (1H, dd, J=9.2, 2.4 Hz), 8.62 (1H, d, J=2.4 Hz),11.10 (1H, s).

Chemical Formula: C₄₁H₄₈ClN₉O₆, Molecular Weight: 798.33.

Total H count from HNMR data: 48.

Exemplary Synthesis of Exemplary Compound 50

N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide

Step 1: Synthesis of tert-butyl4-(2-chloropyridin-4-yl)piperazine-1-carboxylate

To a solution of 4-bromo-2-chloropyridine (5.8 g, 30.2 mmol) in drytoluene (150 mL) was added sodium tert-butoxide (4.3 g, 45.0 mmol),Pd₂(dba)₃ (0.55 g, 0.60 mmol), Xantphos (1.0 g, 1.80 mmol) andtert-butyl piperazine-1-carboxylate (5.6 g, 30.2 mmol). The reactionmixture was stirred at 100° C. for 3 h under nitrogen and then cooled tort. The organic layer was washed with water and brine and then driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified by silica gel chromatography column (PE/EA=8:1) to givetert-butyl 4-(2-chloropyridin-4-yl)piperazine-1-carboxylate (3.6 g, 46%)as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.42 (9H, s), 3.38-3.41 (8H, m), 6.83-6.86(2H, m), 7.96 (1H, d, J=6.0 Hz).

Chemical Formula: C₁₄H₂₀ClN₃O₂, Molecular Weight: 297.78.

Total H count from HNMR data: 20.

Step 2: Synthesis of tert-butyl4-(2-hydrazinylpyridin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(2-chloropyridin-4-yl)piperazine-1-carboxylate (5.0 g, 16.8 mmol) inhydrazine monohydrate (98%, 40 mL), was stirred at 120° C. for 48 hunder nitrogen. Water (100 mL) was added to the mixture. The resultantmixture was extracted by ethyl acetate (50 mL×3), washed by brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated invacuo. The residue (4.8 g, 30% purity) was directly used to the nextstep without further purification as a brown solid.

Step 3: Synthesis of tert-butyl4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(2-hydrazinylpyridin-4-yl)piperazine-1-carboxylate (4.8 g, 30% purity,4.9 mmol) in acetonitrile (100 mL) was added CDI (1.6 g, 9.8 mmol), andthe mixture stirred at 100° C. for 16 h. When it was cooled to roomtemperature, water (100 mL) was added to the reaction. The resultantmixture was extracted by ethyl acetate (100 mL×3), washed by brine (150mL), dried over anhydrous sodium sulfate, filtered, and concentrated invacuo. The residue was purified by column chromatography on silica(DCM/MeOH=20/1) to give tert-butyl4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate(1.2 g, 22% yield for two steps) as a yellow solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100 (v/v)] and 10%[(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] to 10% [(total 10 mMAcONH₄) water/CH₃CN=900/100 (v/v)] and 90% [(total 10 mM AcONH₄)water/CH₃CN=100/900 (v/v)] in 1.6 min, then under this condition for 2.4min, finally changed to 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100(v/v)] and 10% [(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] in 0.1min and under this condition for 0.7 min). Purity is 99.11%, Rt=1.418min. MS Calcd.: 319.7; MS Found: 320.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d⁶) δ 1.42 (9H, s), 3.21-3.23 (4H, m), 3.42-3.43(4H, m), 6.13 (1H, d, J=1.6 Hz), 6.60 (1H, dd, J=8.0, 2.0 Hz), 7.65 (1H,d, J=8.0 Hz), 11.90 (1H, s).

Chemical Formula: C₁₅H₂₁N₅O₃, Molecular Weight: 319.36

Total H count from HNMR data: 21.

Step 4: Synthesis of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate

The solution of tert-butyl4-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate(320 mg, 1.0 mmol), 3-bromopiperidine-2,6-dione (390 mg, 2.0 mmol) andsodium tert-butoxide (120 mg, 1.2 mmol) in acetonitrile (20 mL) wasstirred at 100° C. overnight. When it was cooled to room temperature,water (20 mL) was added. The resultant mixture was extracted by ethylacetate (20 mL×3), washed by brine (30 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by Prep-TLC(DCM/MeOH=20/1) to give tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate(100 mg, 23% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.47 (9H, s), 2.16-2.20 (1H, m), 2.47-2.50(1H, m), 2.66-2.70 (1H, m), 2.90-2.99 (1H, m), 3.31-3.33 (4H, m),3.47-3.49 (4H, m), 5.27-5.31 (1H, m), 6.20 (1H, d, J=1.2 Hz), 6.73 (1H,dd, J=7.6, 2.0 Hz), 7.80 (1H, d, J=8.0 Hz), 11.11 (1H, s).

Chemical Formula: C₂₀H₂₆N₆O₅, Molecular Weight: 430.46.

Total H count from HNMR data: 26.

Step 5: Synthesis of3-(3-oxo-7-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione

To a solution of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazine-1-carboxylate(0.40 g, 0.93 mmol) in dichloromethane (20 mL) was added TFA (8 mL),then stirred at room temperature for 2 h and concentrated in vacuo togive3-(3-oxo-7-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(0.30 g, 98%) as a yellow solid, which was used to the next step withoutfurther purification.

Step 6: Synthesis of tert-butyl4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate

To a solution of3-(3-oxo-7-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)piperidine-2,6-dione(0.30 g, 0.91 mmol) in dry methanol/1,2-dichloroethane/HOAc (20 mL/4mL/0.1 mL) was added tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (0.26g, 0.91 mmol). The mixture was left to stir for 30 min under N₂ gas.Then sodium cyanoborohydride (0.11 g, 1.82 mmol) was added and thereaction mixture was left to stir for 16 h at room temperature. Thesolvent was removed and the residue partitioned between dichloromethaneand water, washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give crude product. The residuewas purified by prep-TLC to give compound tert-butyl4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate(0.20 g, 36%) as a yellow solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100 (v/v)] and 10%[(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] to 10% [(total 10 mMAcONH₄) water/CH₃CN=900/100 (v/v)] and 90% [(total 10 mM AcONH₄)water/CH₃CN=100/900 (v/v)] in 1.6 min, then under this condition for 2.4min, finally changed to 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100(v/v)] and 10% [(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] in 0.1min and under this condition for 0.7 min). Purity is 87.07%, Rt=2.195min.; MS Calcd.: 603.3; MS Found: 604.4 [M+H]⁺.

Step 7: Synthesis of4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoicAcid

To a solution of tert-butyl4-(44(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoate(0.10 g, 0.16 mmol) in dichloromethane (10 mL) was added TFA (5 mL),then stirred at room temperature for 2 h, then concentrated in vacuo togive4-(44(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoicacid (0.075 g, 83%) as a yellow solid, which was used to the next stepwithout further purification.

Step 8: Synthesis ofN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(44(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide

A solution of4-(44(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoicacid (75 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI) (39 mg, 0.21 mmol), 1-hydroxybenzotriazole hydrate(HOBt) (28 mg, 0.21 mmol) and ethyldiisopropylamine (88 mg, 0.69 mmol)in DMF (5 mL) was stirred for 30 min, and then4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile(38 mg, 0.14 mmol) was added. The mixture was stirred at roomtemperature overnight and water (10 mL) was added. The aqueous layer wasextracted by dichloromethane (20 mL×2). The combined organic layer waswashed by brine (10 mL×2), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was purified byprep-HPLC to giveN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide(57 mg, 52%) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6mm*3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min). Purity is 98.22%, Rt=3.022min. MS Calcd.: 807.4; MS Found: 808.3 [M+H]⁺.

HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 5 min). Purity is 99.00%, Rt=10.305min.

¹H NMR (400 MHz, DMSO-d₆) δ 1.13 (6H, s), 1.22 (6H, s), 1.79-1.81 (3H,m), 2.09-2.15 (1H, m), 2.19-2.21 (2H, m), 2.49-2.50 (7H, m), 2.60-2.67(1H, m), 2.76-2.92 (3H, m), 3.22-3.26 (4H, m), 3.86 (2H, d, J=12.8 Hz),4.05 (1H, d, J=9.2 Hz), 4.32 (1H, s), 5.23 (1H, dd, J=12.4, 5.2 Hz),6.12 (1H, s), 6.70 (1H, dd, J=8.0, 1.6 Hz), 6.95 (2H, d, J=9.2 Hz), 7.00(1H, dd, J=8.8, 2.4 Hz), 7.21 (1H, d, J=2.4 Hz), 7.48 (1H, d, J=8.8 Hz),7.72 (3H, t, J=8.4 Hz), 7.91 (1H, d, J=8.8 Hz), 11.04 (1H, s).

Chemical Formula: C₄₃H₅₀ClN₉O₅, Molecular Weight: 808.37.

Total H count from HNMR data: 50.

General Synthetic Scheme C-3 Synthesis of Building BlockN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-formylpiperidin-1-yl)benzamide

Step 1: Synthesis of Ethyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate

To a solution of ethyl 4-fluorobenzoate (27 g, 0.16 mol) in DMSO (500mL) was added K₂CO₃ (44 g, 0.32 mol) and piperidin-4-ylmethanol (32 g,0.19 mol) at 25° C. The resulting solution was stirred at 100° C. for 12h. The reaction was diluted with H₂O (600 mL). The resulting mixture wasextracted with EtOAc (200 mL×3). The combined organic layers were driedover anhydrous sodium sulfate and concentration. The crude product wasslurry in PE/MTBE=1:1 to afford ethyl4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (30 g, 71% yield) as a whitesolid, which was used into next step without further purification.

Chemical Formula: C₁₅H₂₁NO₃; Molecular Weight: 263.34.

¹H NMR (400 MHz, DMSO-d₆): δ 7.91 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz,2H), 4.30-4.35 (m, 2H), 3.90 (d, J=12.8 Hz, 2H), 3.54 (d, J=6.4 Hz, 2H),2.82-2.89 (m, 2H), 1.85 (d, J=12.8 Hz, 2H), 1.71-1.77 (m, 1H), 1.35-1.54(m, 6H).

Total H count from ¹H NMR data: 21

Step 2: Synthesis of 4-(4-(Hydroxymethyl)piperidin-1-yl)benzoic acid

To a solution of ethyl 4-[4-(hydroxymethyl)-1-piperidyl]benzoate (52 g,197.47 mmol, 1 eq) in tetrahydrofuran (250 mL), methanol (250 mL) andwater (250 mL) was added sodium hydroxide (31.6 g, 0.79 mmol, 4 eq). Themixture was stirred at 30° C. for 12 hours. Thin layer chromatography(petroleum ether:ethyl acetate=1:1) showed the reaction was completed.The mixture was adjusted to pH 3-4 with hydrochloric acid (2 M) andfiltered. The filter cake was dried in vacuum. The residue wastriturated with ethyl acetate (500 mL) to give4-[4-(hydroxymethyl)-1-piperidyl]benzoic acid (35 g, 148.76 mmol, 75%yield) as a white solid.

¹H NMR: (400 MHz, DMSO-d₆) δ: 12.19 (s, 1H), 7.74 (d, J=8.8 Hz, 2H),6.93 (d, J=8.8 Hz, 2H), 4.48 (br t, J=5.2 Hz, 1H), 3.90 (d, J=12.8 Hz,2H), 3.27 (br t, J=5.2 Hz, 2H), 2.86-2.72 (m, 2H), 1.72 (d, J=12.8 Hz,2H), 1.66-1.51 (m, 1H), 1.17 (dq, J=4.0, 12.0 Hz, 2H)

Chemical Formula: C₁₃H₁₇NO₃, Molecular Weight: 235.28.

Total H count from HNMR data: 17.

Step 3: Synthesis ofN-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidyl]benzamide

To a solution of 4-[4-(hydroxymethyl)-1-piperidyl]benzoic acid (38 g,161.51 mmol, 1 eq) and4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-chloro-benzonitrile (50.9g, 161.51 mmol, 1 eq, hydrochloride) in dimethylformamide (800 mL) wasadded diisopropylethylamine (83.5 g, 646.04 mmol, 112 mL, 4 eq). Themixture was stirred at 30° C. for 10 min, and theno-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluroniumhexafluorophosphate (64.48 g, 169.59 mmol, 1.05 eq) was added. Themixture was stirred at 30° C. for 1 hour. LCMS showed the reaction wascompleted and desired MS can be detected. The mixture was poured intowater (4 L) and filtered. The filter cake was concentrated andtriturated with methanol (500 mL×2) to giveN-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidyl]benzamide(72 g, 137.89 mmol, 85% yield, 95% purity) as a white solid.

LCMS: MS (ESI) m/z: 496.1 [M+1]⁺

¹H NMR: (400 MHz, DMSO-d₆) δ: 7.90 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz,2H), 7.48 (d, J=9.2 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.00 (dd, J=2.4,8.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 4.48 (t, J=5.2 Hz, 1H), 4.31 (s,1H), 4.05 (d, J=9.2 Hz, 1H), 3.86 (d, J=12.8 Hz, 2H), 3.27 (t, J=5.6 Hz,2H), 2.80-2.70 (m, 2H), 1.73 (d, J=11.2 Hz, 2H), 1.63-1.52 (m, 1H),1.27-1.15 (m, 8H), 1.12 (s, 6H).

Chemical Formula: C₂₈H₃₄ClN₃O₃, Molecular Weight: 496.04.

Total H count from HNMR data: 34.

Step 4: Synthesis ofN-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-formyl-1-piperidyl)benzamide

To a solution ofN-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidyl]benzamide(65 g, 131.04 mmol, 1 eq) in dichloromethane (700 mL) was addedDess-Martin reagent (76.70 g, 180.83 mmol, 1.38 eq). The mixture wasstirred at 30° C. for 2 hours. Thin layer chromatography(dichloromethane:methanol=1:1) showed the reaction was completed. Thereaction was adjusted to pH 8-9 with saturated sodium bicarbonate. Themixture was diluted with water (3 L) and extracted with dichloromethane(1.5 L x 3). The combined organic phase was washed with saturated brine(1.5 L x 2), dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (dichloromethane:methanol=100:0 to 50:1) to giveN-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-formyl-1-piperidyl)benzamide(34.6 g, 67.94 mmol, 51% yield, 97% purity) as a white solid.

¹H NMR: (400 MHz, DMSO-d₆) δ: 9.63 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.74(d, J=8.8 Hz, 2H), 7.49 (d, J=9.2 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H),7.03-6.94 (m, 3H), 4.32 (s, 1H), 4.05 (d, J=9.2 Hz, 1H), 3.76 (td,J=3.6, 12.8 Hz, 2H), 3.01-2.92 (m, 2H), 2.62-2.55 (m, 1H), 2.62-2.55 (m,1H), 1.92 (dd, J=3.6, 12.8 Hz, 2H), 1.62-1.48 (m, 2H), 1.21 (s, 6H),1.12 (s, 6H).

Chemical Formula: C₂₈H₃₂ClN₃O₃, Molecular Weight: 494.02.

Total H count from HNMR data: 32.

General Synthetic Scheme C-4 Synthesis of building blockN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-oxoethyl)piperidin-1-yl)benzamide

Step 1: Synthesis of benzyl 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate

Into a 100-mL round-bottom flask, was placed benzyl 4-fluorobenzoate(2.3 g, 10.0 mmol, 1.0 equiv), N,N-dimethylformamide (30.0 mL),2-(piperidin-4-yl)ethan-1-ol (1.3 g, 10.0 mmol, 1.0 equiv),N,N-Diisopropylethylamine (3.87 g, 29.9 mmol, 4.0 equiv). The resultingsolution was stirred for 12 h at 90° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1/1). This resulted in 2.1 g(62%) of benzyl 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate as a yellowsolid.

LC-MS (ES⁺): 340.25m/z [MH⁺], t_(R)=1.20 min, (1.90 minute run).

Step 2: Synthesis of 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoic acid

To a solution of benzyl 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoate(500 mg, 1.47 mmol, 1.00 equiv) in 20.0 mL methyl alcohol (30.0 mL) wasadded Pd/C (10%, 300 mg) under nitrogen atmosphere in a 100.0 mL roundbottom flask. The flask was then vacuumed and flushed with hydrogen. Thereaction mixture was hydrogenated at room temperature for 12 hours underhydrogen atmosphere using a hydrogen balloon, then filtered through aCelite pad and concentrated under reduced pressure. This resulted in300.0m g (82.0%) of 4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoic acid asa yellow solid.

LC-MS (ES⁺): 250.00m/z [MH⁺], t_(R)=0.74 min, (2.00 minute run).

Step 3: Synthesis of4-[4-(2-hydroxyethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

Into a 100-mL round-bottom flask, was placed4-[4-(2-hydroxyethyl)piperidin-1-yl]benzoic acid (300.0 mg, 1.2 mmol,2.0 equiv), N,N-dimethylformamide (10.0 g, 136.8 mmol, 227.0 equiv),N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (686 mg, 1.8 mmol, 3.0 equiv),2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrilehydrochloride (190.0 mg, 0.6 mmol, 1.0 equiv), N,N-Diisopropylethylamine(466.0 mg, 3.6 mmol, 6.0 equiv). The resulting solution was stirred for1 h at room temperature. The reaction was then quenched by the additionof 60 mL of water. The resulting solution was extracted with 3×30 mL ofethyl acetate and the organic layers combined and dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 250.0 mg (81%) of4-[4-(2-hydroxyethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamideas a yellow solid.

LC-MS (ES⁺): 510.25m/z [MH⁺], t_(R)=1.35 min, (1.90 minute run).

Step 4: Synthesis of4-[4-(2-oxoethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

Into a 100-mL round-bottom flask, was placed4-[4-(2-hydroxyethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide(200.0 mg, 0.4 mmol, 1.0 equiv), dichloromethane (20.0 mL), Dess-Martin(249.0 mg, 0.60 mmol, 1.5 equiv). The resulting solution was stirred for4 h at room temperature. The resulting solution was extracted with ofethyl acetate and the organic layers combined and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 80.0 mg (40%) of4-[4-(2-oxoethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamideas a yellow solid.

LC-MS (ES⁺): 508.20m/z [MH⁺], t_(R)=1.19 min, (2.00 minute run).

Exemplary Synthesis of Exemplary Compound 51

rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide

Step 1: Synthesis of 3,4-dimethyl 6-chloropyridine-3,4-dicarboxylate

Into a 100-mL round-bottom flask, was placed6-chloropyridine-3,4-dicarboxylic acid (200.0 mg, 1.0 mmol, 1.0 equiv),methanol (5.0 mL), acetonitrile (5.0 mL), TMSCHN2 (2.0 mL),N,N-Diisopropylethylamine (516.0 mg, 4.0 mmol, 4.0 equiv). The resultingsolution was stirred for 2 h at room temperature. The reaction was thenquenched by the addition of water (30 mL). The resulting solution wasextracted with ethyl acetate (20.0 mL×3) and the organic layers combinedand concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1). The resulting mixturewas concentrated under vacuum. This resulted in 220 mg (96%) of3,4-dimethyl 6-chloropyridine-3,4-dicarboxylate as a yellow solid.

LC-MS (ES⁺): 230.10m/z [MH⁺], t_(R)=1.01 min, (1.90 minute run).

Step 2: Synthesis of 3,4-dimethyl6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylate

Into a 100-mL round-bottom flask, was placed 3,4-dimethyl6-chloropyridine-3,4-dicarboxylate (200.0 mg, 0.9 mmol, 1.0 equiv),N,N-dimethylformamide (5.0 mL), tert-butyl piperazine-1-carboxylate(325.0 mg, 1.7 mmol, 2.0 equiv), N,N-Diisopropylethylamine (450.0 mg,3.5 mmol, 4.0 equiv). The resulting solution was stirred for 2 h at 100°C. The reaction was then quenched by the addition of water (80 mL). Theresulting solution was extracted with ethyl acetate (30.0 mL×3) and theorganic layers combined and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:3). This resulted in 320.0 mg (97%) of 3,4-dimethyl6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylate asa yellow solid.

LC-MS (ES⁺): 380.10m/z [MH⁺], t_(R)=1.19 min, (2.0 minute run).

Step 3: Synthesis of6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylicAcid

Into a 100-mL round-bottom flask, was placed 3,4-dimethyl6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylate(320.0 mg, 0.8 mmol, 1.0 equiv), methanol (10.0 mL), water (5 mL),lithium hydroxide (96 mg, 4 mmol, 5 equiv). The resulting solution wasstirred for 5 h at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 300.0 mg (101%) of6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylicacid as a white solid.

LC-MS (ES⁺): 296.20m/z [MH⁺], t_(R)=0.52 min, (1.90 minute run).

Step 4: Synthesis of3-[1,3-dioxo-6-(piperazin-1-yl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2,6-dione

Into a 100-mL round-bottom flask, was placed6-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyridine-3,4-dicarboxylicacid (300.0 mg, 0.8 mmol, 1.0 equiv), acetic acid (20.0 mL),3-aminopiperidine-2,6-dione (218 mg, 1.7 mmol, 2.0 equiv). The resultingsolution was stirred for 2 h at 130° C. The reaction was then quenchedby the addition of water (30 mL). The resulting solution was extractedwith ethyl acetate (30 mL×3) and the organic layers combined and driedin an oven under reduced pressure. and concentrated under vacuum. Theresidue was applied onto a silica gel column withdichloromethane/methanol (3:1). This resulted in 60.0 mg (20%) of3-[1,3-dioxo-6-(piperazin-1-yl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2,6-dioneas a yellow solid.

LC-MS (ES⁺): 344.20m/z [MH⁺], t_(R)=0.66 min, (1.90 minute run).

Step 5: Synthesis of4-[4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl]ethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

Into a 100-mL round-bottom flask, was placed3-[1,3-dioxo-6-(piperazin-1-yl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]piperidine-2,6-dionehydrochloride (60.0 mg, 0.2 mmol, 1.0 equiv), dichloromethane (10 mL),4-[4-(2-oxoethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide(80.0 mg, 0.1 mmol, 1.0 equiv), Sodium triacetoxyborohydride (110.0 mg,3.0 equiv). The resulting solution was stirred for 4 h at roomtemperature. The reaction was then quenched by the addition of 40 mL ofwater. The resulting solution was extracted with dichloromethane (20mL×3) and the organic layers combined and concentrated under vacuum. Thecrude product (4.0 mL) was purified by Prep-HPLC with the followingconditions: Column, Sunfire Prep C18 OBD Column, 10 um, 19*250 mm;mobile phase, Water (0.1% formic acid) and acetonitrile (30.0%acetonitrile up to 52.0% in 8 min); Detector, UV 254 nm. 5.0 mL productwas obtained. This resulted in 50.5 mg (38.2%) of4-[4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]piperazin-1-yl]ethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamideas a yellow solid.

1H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.57 (s, 1H), 7.87 (d, J=8.7Hz, 1H), 7.70 (d, J=8.6 Hz, 2H), 7.44 (d, J=9.1 Hz, 1H), 7.29 (s, 1H),7.17 (d, J=2.2 Hz, 1H), 7.02-6.87 (m, 3H), 5.07 (dd, J=12.8, 5.3 Hz,1H), 4.29 (s, 1H), 4.02 (d, J=9.1 Hz, 1H), 3.28 (s, 5H), 2.59-2.41 (m,9H), 2.00 (t, J=11.3 Hz, 1H), 1.73 (d, J=12.8 Hz, 2H), 1.45 (s, 3H),1.14 (d, J=27.2 Hz, 14H).

LC-MS (ES⁺): 835.25m/z [MH⁺], t_(R)=2.56 min, (4.80 minute run).

Exemplary Synthesis of Exemplary Compound 52

(rac)-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide

Step 1: Synthesis of tert-butyl 4-carbamimidoylpiperazine-1-carboxylate

Into a 250-mL round-bottom flask, was placed tert-butylpiperazine-1-carboxylate (10 g, 53.69 mmol, 1.00 equiv), i-propanol (150mL), (methylsulfanyl)methanimidamide (7.4 g, 82.09 mmol, 1.00 equiv),DIEA (25 mL, 3.00 equiv). The resulting solution was stirred for 24 h at100° C. in an oil bath. The resulting mixture was concentrated undervacuum. The resulting solution was diluted with acetonitrile (150 mL),then stirred for 30 min. The solids were collected by filtration. Thisresulted in 11.5 g (94%) of tert-butyl4-carbamimidoylpiperazine-1-carboxylate as a white solid.

Step 2: Synthesis of 1,4-diethyl(2Z)-2-[(dimethylamino)methylidene]-3-oxobutanedioate

Into a 250-mL round-bottom flask, was placed 1,4-diethyl2-oxobutanedioate (10 g, 53.14 mmol, 1.00 equiv), DMFDMA (12.65 g,106.30 mmol, 2.00 equiv) at 0° C. The resulting solution was stirred for2 h at room temperature. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (7/3). This resulted in 2.79 g(22%) of 1,4-diethyl(2Z)-2-[(dimethylamino)methylidene]-3-oxobutanedioate as yellow oil.

LC-MS (ES⁺): m/z 243.95 [MH⁺], t_(R)=0.64 min, (1.90 minute run).

Step 3: Synthesis of 4,5-diethyl2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylate

Into a 250-mL round-bottom flask, was placed tert-butyl4-carbamimidoylpiperazine-1-carboxylate (1.0 g, 4.38 mmol, 1.00 equiv),ethanol (20 mL), 1,4-diethyl(2Z)-2-[(dimethylamino)methylidene]-3-oxobutanedioate (1.065 g, 4.38mmol, 1.00 equiv), EtONa (596 mg, 8.76 mmol, 1.00 equiv). The resultingsolution was stirred for 2 h at 75° C. in an oil bath. The resultingmixture was concentrated under vacuum. The resulting solution wasextracted with ethyl acetate (100 mL) and the organic layers combined.The resulting mixture was washed with brine (100 mL). The mixture wasdried over anhydrous sodium sulfate. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1/5). Thisresulted in 873.0 mg (49%) of 4,5-diethyl2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylateas light yellow oil.

LC-MS (ES⁺): m/z 409.20 [MH⁺], t_(R)=1.19 min, (1.90 minute run).

Step 4: Synthesis of2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylicAcid

Into a 100-mL round-bottom flask, was placed 4,5-diethyl2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylate(873.0 mg, 2.14 mmol, 1.00 equiv), ethanol/water (5/2) (14 mL), lithiumhydroxide (256.7 mg, 10.72 mmol, 5.00 equiv). The resulting solution wasstirred for 8 h at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 1.02 g (crude) of2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylicacid as a white solid.

LC-MS (ES⁺): m/z 352.45 [MH⁺], t_(R)=0.73 min, (1.90 minute run).

Step 5: Synthesis of tert-butyl4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl]piperazine-1-carboxylate

Into a 100-mL round-bottom flask, was placed2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]pyrimidine-4,5-dicarboxylicacid (735.0 mg, 2.09 mmol, 1.00 equiv). This was followed by theaddition of acetic anhydride (10 mL), after stirred 2h at 130° C.,concentrated under vacuum. To this was added pyridine (10 mL),3-aminopiperidine-2,6-dione hydrochloride (445.0 mg, 2.70 mmol, 1.30equiv). The resulting solution was stirred overnight at 120° C. in anoil bath. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with dichloromethane (100 mL). The solidswere filtered out. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (7/3). This resulted in 243.0 mg (26%) oftert-butyl4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl]piperazine-1-carboxylateas brown oil.

LC-MS (ES⁺): m/z 467.10 [M Nat], t_(R)=1.10 min, (2.00 minute run).

Step 6: Synthesis of3-[5,7-dioxo-2-(piperazin-1-yl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl]piperidine-2,6-dione

Into a 50-mL round-bottom flask, was placed tert-butyl4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl]piperazine-1-carboxylate(243.0 mg, 0.55 mmol, 1.00 equiv), dichloromethane (5.0 mL),trifluoroacetic acid (2.0 mL). The resulting solution was stirred for 2h at room temperature. The resulting mixture was concentrated undervacuum. This resulted in 320.0 mg (crude) of3-[5,7-dioxo-2-(piperazin-1-yl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl]piperidine-2,6-dioneas brown oil.

LC-MS (ES⁺): m/z 345.25 [MH⁺], t_(R)=0.61 min, (1.90 minute run).

Step 7: Synthesis of4-[4-(2-[4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl]piperazin-1-yl]ethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

Into a 100-mL round-bottom flask, was placed4-[4-(2-oxoethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide(90 mg, 0.18 mmol, 1.00 equiv), dichloromethane (10 mL),3-[5,7-dioxo-2-(piperazin-1-yl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-6-yl]piperidine-2,6-dione(61.24 mg, 0.18 mmol, 1.00 equiv). This was followed by the addition ofDIEA (0.5 mL), after stirred at 30° C. for 1 h. To this was addedNaBH(OAc)₃ (122.89 mg, 0.58 mmol, 3.00 equiv). The resulting solutionwas stirred for 5 h at 30° C. in an oil bath. The resulting solution wasextracted with dichloromethane (150 mL) and the organic layers combined.The resulting mixture was washed with brine (50 mL). The mixture wasdried over anhydrous sodium sulfate and concentrated under vacuum. Thecrude product was purified by Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase,water (10 mmol/L bicarbonate amine) and acetonitrile (30.0% acetonitrileup to 51.0% in 8 min); Detector, UV 254 nm. This resulted in 50 mg (34%)of4-[4-(2-[4-[6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl]piperazin-1-yl]ethyl)piperidin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamideas a yellow solid.

¹H NMR (400 MHz, d6-DMSO): δ 11.12 (s, 1H), 8.90 (s, 1H), 7.91-7.89 (d,J=8.4 Hz, 1H), 7.74-7.72 (d, J=7.6 Hz, 2H), 7.49-7.47 (d, J=8.8 Hz, 1H),7.20 (s, 1H), 6.99-6.94 (m, 3H), 5.16-5.13 (m, 1H), 4.32 (s, 1H),4.06-3.83 (m, 7H), 2.88-2.57 (m, 5H), 2.39-2.33 (m, 2H), 2.07-2.01 (m,1H), 1.78-1.75 (m, 2H), 1.54-1.35 (m, 3H), 1.21 (m, 8H), 1.12 (s, 6H);LC-MS (ES⁺): m/z 836.45/838.45 [MH⁺], t_(R)=2.17 min, (2.95 minute run).

Chemical formula: C₄₄H₅₀ClN₉O₆ [835.36/837.36].

Total H count from HNMR data: 50.

D. Exemplary Synthetic Schemes for Exemplary BRaf Targeting Moiety BasedCompounds

General Synthetic Approach

The synthetic realization and optimization of the bifunctional moleculesas described herein may be approached in a step-wise or modular fashion.For example, identification of compounds that bind to the targetmolecules can involve high or medium throughput screening campaigns ifno suitable ligands are immediately available. It is not unusual forinitial ligands to require iterative design and optimization cycles toimprove suboptimal aspects as identified by data from suitable in vitroand pharmacological and/or ADMET assays. Part of the optimization/SARcampaign would be to probe positions of the ligand that are tolerant ofsubstitution and that might be suitable places on which to attach thelinker chemistry previously referred to herein. Where crystallographicor NMR structural data are available, these can be used to focus such asynthetic effort.

In a very analogous way one can identify and optimize ligands for an E3Ligase, i.e. ULMs/ILMs/VLMs/CLMs/ILMs.

With PTMs and ULMs (e.g. ILMs, VLMs, CLMs, and/or ILMs) in hand, oneskilled in the art can use known synthetic methods for their combinationwith or without a linker moiety. Linker moieties can be synthesized witha range of compositions, lengths and flexibility and functionalized suchthat the PTM and ULM groups can be attached sequentially to distal endsof the linker. Thus a library of bifunctional molecules can be realizedand profiled in in vitro and in vivo pharmacological and ADMET/PKstudies. As with the PTM and ULM groups, the final bifunctionalmolecules can be subject to iterative design and optimization cycles inorder to identify molecules with desirable properties.

In some instances, protecting group strategies and/or functional groupinterconversions (FGIs) may be required to facilitate the preparation ofthe desired materials. Such chemical processes are well known to thesynthetic organic chemist and many of these may be found in texts suchas “Greene's Protective Groups in Organic Synthesis” Peter G. M. Wutsand Theodora W. Greene (Wiley), and “Organic Synthesis: TheDisconnection Approach” Stuart Warren and Paul Wyatt (Wiley).

A compound of formula XVI may be reacted with a reagent II′(commercially available or readily prepared using standard reactiontechniques known to one skilled in the art) under Chan-Lamcross-coupling conditions, e.g. copper (II) acetate, pyridine ordiethylamine or triethylamine, 100° C., to produce a compound of formulaXVII. M′ represents a boronic acid or boronic ester; Ar represents anaromatic or heteroaromatic ring system; L represents an optional linker,represents a primary or secondary amine, optionally cyclized into a 4 to8 membered heterocyclic ring, wherein PG represents a suitableprotecting group, including but not limited to t-butoxycarbonyl orbenzyl. Compounds of formula XVII may be may be reacted with a reagentXVIII under palladium-catalyzed cross-coupling conditions, e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium,tri-tert-butylphosphine tetrafluoroborate, cesium fluoride, 1,4-dioxane,90° C., to produce a compound of formula XIX. M represents a functionalgroup capable of undergoing palladium-catalyzed transmetallation, e.g. aboronic acid, boronic ester, or trialkylstannane and Ar′ represents anaromatic or heteroaromatic ring system with optional substituents. Acompound of formula XIX may then be converted to a compound of formulaXX by treatment with a reagent suitable for the removal of PG, e.g.hydrogen chloride in 1,4-dioxane or methanol when PG is t-butyl. Acompound of formula XX may also be reacted with a compound of formulaVII to provide compounds of formula XXI, wherein X is a suitable leavinggroup such as fluorine or chlorine, Y is C═O, the aromatic ring of VIImay have further optional substituents, and reaction conditions arethose for a nucleophilic aromatic substitution, e.g. triethylamine,DMSO, 80° C. In cases where the group Ar′ contains optionalsubstituents, e.g. a ketone, these may undergo furtherfunctionalization, e.g. by treatment with hydroxylamine hydrochlorideand pyridine at room temperature, to provide further compounds offormula XXI.

Alternatively, a compound of formula XVII may be converted to a compoundof formula XXII by using conditions analogous to those for theconversion of XIX to XX in Scheme 5. A compound of formula XXII may thenbe treated with a compound of formula VII as defined in Scheme 5 toproduce a compound of formula XXIII The compound of formula XXIII maythen be treated with a reagent XVIII as defined in Scheme 5 to produce acompound of formula XXI. In cases where the group Ar′ contains optionalsubstituents, e.g. a ketone, these may undergo furtherfunctionalization, e.g. by treatment with hydroxylamine hydrochlorideand pyridine at room temperature, to provide further compounds offormula XXI.

Exemplary Synthesis of Exemplary Compound 42(E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-methylisoindoline-1,3-dione

Step A:2-(2,6-dioxopiperidin-3-yl)-4-methyl-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione

To a solution of4-chloro-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione(100 mg, 0.14 mmol) in 1,4-dioxane 10 mL and H₂O 1 mL were addedmethylboronic acid (33.6 mg, 0.56 mmol), Pd(aMPhos)C12 (9.9 mg, 0.014mmol), and CsF (85.12 mg, 0.56 mmol). The resulting solution wasirradiated at 90° C. with MW for 2 h. After cooling to rt, it wasdiluted with EA (50 mL), and the mixture was washed with brine (3×20mL). The organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by prep-TLC to afford2-(2,6-dioxopiperidin-3-yl)-4-methyl-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione(70 mg, 72.1% yield). LCMS (ES⁺): m/z 706.3 [M+H]⁺.

Step B: (E)-2-(2,6-dioxopiperidin-3-yl)-5 (4 (4 (4 (1(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-methylisoindoline-1,3-dione

To a solution of2-(2,6-dioxopiperidin-3-yl)-4-methyl-5-(4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)isoindoline-1,3-dione(70 mg, 0.10 mmol) in acetonitrile 3 mL and pyridine 3 mL was addedhydroxylamine hydrochloride (69.5 mg, 1.0 mmol). The mixture was stirredat 40° C. for 20 min. Then it was diluted with DCM (20 mL), and themixture was washed with brine (10 mL). The organic phase wasconcentrated and purified by prep-TLC to afford(E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-methylisoindoline-1,3-dione(19.6 mg, 27.8% yield) as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 11.09 (s, 1H), 10.89 (s, 1H), 8.72 (s, 1H),8.58-8.57 (m, 2H), 7.83 (d, J=8.0 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.56(d, J=7.6 Hz, 1H), 7.50-7.41 (m, 4H), 7.23-7.17 (m, 3H), 5.13-5.09 (m,1H), 3.61-3.42 (m, 8H), 3.04-2.97 (m, 2H), 2.93-2.82 (m, 3H), 2.62-2.56(m, 5H), 2.08-2.00 (m, 1H); LCMS (ES⁺): m/z 721.3 [M+H]⁺.

Exemplary Compound 41 may be prepared by a procedure analogous to thatdescribed for Exemplary Compound 42.

E. Exemplary Synthetic Schemes for Exemplary BRD4 Binding Moiety BasedCompounds Exemplar Synthesis of Exemplary Compound 45:2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide

Step 1: Preparation of 2-amino-4-hydroxybenzoic Acid

A mixture of 2-amino-4-methoxybenzoic acid (1.0 g, 5.98 mmol), redphosphorus (556 mg, 17.94 mmol) and 55% hydroiodic acid (10 mL) washeated at 100° C. for 14 h in a sealed tube. The reaction mixture waspoured into ice water. The pH of the solution was adjusted to 6-7 bysodium carbonate. The solution was extracted with ethyl acetate (20mL×3). The combined organic phases were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum to afford crude2-amino-4-hydroxybenzoic acid (400 mg, 44% yield) which was used in thenext step without further purification. ¹HNMR (400 MHz, DMSO-d₆): δ7.53-7.55 (m, 1H), 6.12 (s, 1H), 5.99-6.02 (m, 1H).

Step 2: Preparation of 2-acetamido-4-acetoxybenzoic Acid

To a mixture of 2-amino-4-hydroxybenzoic acid (400 mg, 2.61 mmol) andimidazole (888 mg, 10.06 mmol) in acetonitrile (20 mL) was added acetylchloride (789 mg, 10.06 mmol) dropwise at 0° C. The solution was stirredat rt for 10 h and then quenched by water (40 mL). The mixture wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and filtered.Volatiles were evaporated in vacuum and the residue was purified bycolumn chromatography (ethyl acetate/petroleum ether=2:1) to afford2-acetamido-4-acetoxybenzoic acid (350 mg, 57% yield). ¹HNMR (400 MHz,DMSO-d₆): δ 11.19 (s, 1H), 8.30 (s, 1H), 8.01-8.03 (m, 1H), 6.92-6.95(m, 1H), 2.30 (s, 3H), 2.15 (s, 3H).

Step 3: Preparation of3-(7-hydroxy-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione

To a mixture of 2-acetamido-4-acetoxybenzoic acid (400 mg, 1.69 mmol),3-aminopiperidine-2,6-dione hydrochloride (333 mg, 2.02 mmol), triphenylphosphite (2.0 mL) in acetonitrile (10 mL) was added imidazole (383 mg,5.63 mmol). The reaction solution was heated to reflux for 10 h. Thesolution was evaporated under reduced pressure and the residue wasre-crystallized (20% ethyl acetate in hexane) to afford3-(7-Hydroxy-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (110mg, 19% yield). ¹HNMR (400 MHz, DMSO-d⁶): δ 10.94 (s, 1H), 10.51 (s,1H), 7.84-7.86 (m, 1H), 6.92-6.94 (m, 1H), 6.85 (s, 1H), 5.16-5.20 (m,1H), 2.73-2.85 (m, 1H), 2.58-2.63 (m, 5H), 2.13-2.15 (m, 1H).

Step 4: Preparation of tert-butyl(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)carbamate

To a mixture of3-(7-hydroxy-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (161mg, 0.348 mmol) and2-(2-(2-(2-(4-((tert-butoxycarbonyl)amino)phenoxy)ethoxy)ethoxy)ethoxy)ethylmethanesulfonate (100 mg, 0.348 mmol, prepared according to proceduresof similar intermediate described in US 2015/0291562) in DMF (5.0 mL)was added sodium carbonate (74 mg, 0.696 mmol). The mixture was stirredat 80° C. for 6 h. The resulting mixture was cooled to rt. Ethyl acetate(30 mL) was added and the organic layer was washed with water and brine.The organic layer was dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The residue was purification bypreparative TLC to afford tert-butyl(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)carbamate(55.4 mg, 24% yield). ¹HNMR (400 MHz, DMSO-d⁶): δ 10.98 (s, 1H), 9.08(s, 1H), 7.91-7.93 (m, 1H), 7.32-7.34 (m, 2H), 7.07-7.09 (m, 2H),6.82-6.84 (m, 2H), 5.20-5.24 (m, 1H), 4.24 (s, 2H), 3.99 (m, 2H), 3.79(m, 2H), 3.70-3.71 (m, 2H), 3.56-3.60 (m, 8H), 2.79-2.87 (m, 1H),2.57-2.70 (m, 5H), 2.17-2.18 (m, 1H), 1.47 (s, 9H). LC-MS: (ES⁺): m/z655.3 [M+H]⁺.

Step 5: Preparation of2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide(Exemplary Compound 45)

To a pre-mixed solution containing(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (6.11 mg, 0.01525 mmol) in DMF (2.00 ml), TBTU (7.34 mg, 0.02287mmol) and DIPEA (7.96 μL, 0.04575 mmol) was added3-(7-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione(8.46 mg, 0.01525 mmol, prepared by treating the product from step 4with HCl in dioxane) and the mixture was left to stir for 2 h. Themixture was diluted with ethyl acetate and water. The organic layer waswashed with sodium bicarbonate, water (3×) and brine. The resultingsolution was filtered through a thin pad of silica gel and thenconcentrated in vacuo to give a crude solid. This material was purifiedby silica gel chromatography on a Teledyne Combiflash ISCO eluting withMeOH/DCM (0:100 to 7:93) to yield2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-a][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(24(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide(10.1 mg, 0.01077 mmol, 71.1% yield). ¹H NMR (400 MHz, methanol-d₄) δ8.55 (s, 1H), 7.96-8.00 (m, 1H), 7.36-7.50 (m, 6H), 7.03-7.09 (m, 2H),6.87 (dd, J=3.03, 9.10 Hz, 2H), 5.22 (td, J=5.40, 10.91 Hz, 1H),4.70-4.74 (m, 1H), 4.22 (d, J=3.33 Hz, 2H), 4.10 (d, J=4.30 Hz, 2H),3.85-3.91 (m, 2H), 3.79-3.84 (m, 2H), 3.64-3.71 (m, 7H), 3.55-3.64 (m,2H), 3.42-3.50 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=3.33 Hz, 2H), 2.44 (d,J=3.33 Hz, 3H), 1.89 (s, 3H), 1.68 (d, J=3.33 Hz, 2H), 1.29 (br. s.,3H). LC/MS (ES⁺): m/z 937.19/939.19 [M+H]⁺.

Exemplar Synthesis of Exemplary Compound 44:2-0S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-a][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide

This molecule was synthesized using the same method as described inExample 1. The key intermediate was prepared according the scheme listedabove. ¹H NMR (400 MHz, methanol-d4) □ 8.55 (s, 1H), 7.96-8.00 (m, 1H),7.36-7.50 (m, 6H), 7.03-7.09 (m, 2H), 6.87 (dd, J=3.03, 9.10 Hz, 2H),5.22 (td, J=5.40, 10.91 Hz, 1H), 4.70-4.74 (m, 1H), 4.22 (d, J=3.33 Hz,2H), 4.10 (d, J=4.30 Hz, 2H), 3.85-3.91 (m, 2H), 3.79-3.84 (m, 2H),3.64-3.71 (m, 7H), 3.55-3.64 (m, 2H), 3.42-3.50 (m, 2H), 2.71 (s, 3H),2.66 (d, J=3.33 Hz, 2H), 2.44 (d, J=3.33 Hz, 3H), 1.89 (s, 3H), 1.68 (d,J=3.33 Hz, 2H), 1.29 (br. s., 3H). LCMS (ES⁺): m/z 937.19/939.19 [M+H]⁺.

Exemplary Synthesis of Exemplar Compound 43:2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-a][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((1-oxo-2-((S)-6-oxopiperidin-3-yl)isoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide

The key intermediate for the preparation of this compound wassynthesized according the scheme listed above. The final step of amidecoupling was carried out under the same condition as described inExample 1. ¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 7.45 (dd, J=8.71,13.21 Hz, 4H), 7.31-7.37 (m, 3H), 7.24 (d, J=7.24 Hz, 1H), 6.84 (d,J=9.00 Hz, 2H), 6.78 (d, J=8.02 Hz, 1H), 6.75 (br. s., 1H), 4.66-4.73(m, 2H), 4.20 (d, J=2.74 Hz, 1H), 4.07-4.12 (m, 2H), 3.80-3.90 (m, 3H),3.64-3.77 (m, 10H), 3.52-3.58 (m, 1H), 3.35-3.42 (m, 3H), 2.68 (br. s.,3H), 2.52-2.59 (m, 2H), 2.41 (s, 3H), 2.02-2.08 (m, 2H), 1.69 (s, 3H),1.26 (s, 3H). LC-MS (ES⁺): m/z 895.22/897.22 [M+H]⁺.

Protein Level Control

This description also provides methods for the control of protein levelswith a cell. This is based on the use of compounds as described herein,which are known to interact with a specific target protein such thatdegradation of a target protein in vivo will result in the control ofthe amount of protein in a biological system, preferably to a particulartherapeutic benefit.

The following examples are used to assist in describing the presentinvention, but should not be seen as limiting the present invention inany way.

Exemplary Embodiments of the Present Disclosure

The present disclosure encompasses the following specific embodiments.These following embodiments may include all of the features recited in aproceeding embodiment, as specified. Where applicable, the followingembodiments may also include the features recited in any proceedingembodiment inclusively or in the alternative.

An aspect of the present disclosure provides a cereblon E3 ubiquitinligase binding compound having a chemical structure selected from:

wherein:

-   -   W is selected from the group consisting of CH₂, CHR, C═O, SO₂,        NH, N, optionally substituted cyclopropyl group, optionally        substituted cyclobutyl group, and N-alkyl;    -   W₃ is selected from C or N;    -   each X is independently selected from the group consisting of O,        S, and H₂,    -   Y is selected from the group consisting of CH₂, —C═CR′, NH,        N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and        S;    -   Z is selected from the group consisting of O, S, and H₂;    -   G and G′ are independently selected from the group consisting of        H, alkyl (linear, branched, optionally substituted), OH,        R′OCOOR, R′OCONRR″, CH₂-heterocyclyl optionally substituted with        R′, and benzyl optionally substituted with R′;    -   Q₁, Q₂, Q₃, and Q₄ represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   A is independently selected from the group H, alkyl (linear,        branched, optionally substituted), cycloalkyl, Cl and F;    -   R comprises —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″,        —CR′R″—, —CR′NR′R″—, (—CR′O)_(n)—R″, R″, -aryl, -hetaryl, -alkyl        (linear, branched, optionally substituted), -cycloalkyl,        -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″,        —OP(O)R′R″, —Cl, —F, —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″,        —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″,        —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′,        —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and        —OCF₃;    -   R′ and R″ are independently selected from the group consisting        of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic,        —C(═O)R, heterocyclyl, each of which is optionally substituted;    -   n′ integer from 1-10;    -   represents a single bond or a double bond;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and Rn comprises 1-4 independent functional        groups, optionally substituted linear or branched alkyl (e.g., a        C₁-C₆ linear or branched alkyl optionally substituted with one        or more halogen, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl        (e.g., C5-C7 aryl)), optionally substituted aryl (e.g., an        optionally substituted C5-C7 aryl), optionally substituted        alkyl-aryl (e.g., an alkyl-aryl comprising at least one of an        optionally substituted C1-C6 alkyl, an optionally substituted        C5-C7 aryl, or combinations thereof), optionally substituted        alkoxyl group (e.g., a methoxy, ethoxy, butoxy, propoxy,        pentoxy, or hexoxy; wherein the alkoxyl may be substituted with        one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl        (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)),        optionally substituted

(e.g., optionally substituted with one or more halogen, alkyl, haloalky,fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7aryl)), optionally substituted

(e.g., optionally substituted with one or more halogen, alkyl, haloalky,fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7aryl)), or atoms; and each of x, y, and z are independently 0, 1, 2, 3,4, 5, or 6, n is an integer from 1-10 (e.g., 1-4).

Another aspect of the present disclosure provides a bifunctionalcompound having the chemical structure:

CLM-L-PTM,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer,solvate, polymorph or prodrug thereof,

wherein:

-   -   the PTM is a small molecule comprising a protein targeting        moiety;    -   the L is a bond or a chemical linking moiety covalently coupling        the CLM and the PTM; and    -   the CLM is a small molecule cereblon E3 ubiquitin ligase binding        moiety of claim 1, wherein when n is 2, 3, or 4, then at least        one of R. or W is modified to be covalently joined to the linker        group (L) or a PTM.

In any aspect or embodiment described herein, the CLM is linked to thePTM, the chemical linker group (L), or a combination thereof via W, X,R¹, R², R³, R⁴, R′, Q₁, Q₂, Q₃, Q₄, and Q₅.

In any aspect or embodiment described herein, the PTM is a moiety thatbinds BRD4, BRaf, Estrogen Receptor (ER), or Androgen Receptor (AR).

In any aspect or embodiment described herein, the compound may furthercomprise a second E3 ubiquitin ligase binding moiety coupled through alinker group.

In any aspect or embodiment described herein, the second E3 ubiquitinligase binding moiety binds or targets an E3 ubiquitin ligase selectedfrom the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM),mouse double-minute homolog2 (MLM), and inhibitors of apoptosis proteins(ILM).

In any aspect or embodiment described herein, the CLM is represented bya chemical structure selected from the group consisting of:

In any aspect or embodiment described herein, the linker (L) comprises achemical structural unit represented by the formula:

-(A^(L))_(q)-

wherein:

-   -   (A^(L))_(q) is a group which is connected to at least one of the        CLM, the PTM, or a combination thereof;    -   q is an integer greater than or equal to 1;    -   each A^(L) is independently selected from the group consisting        of, a bond, CR^(L1)R^(L2), O, S, SO, SO₂, NR¹³, SO₂NR¹³,        SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO,        CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1),        NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4),        C₃₋₁₁cycloalkyl optionally substituted with 0-6 R^(L1) and/or        R^(L2) groups, C₃₋₁₁heterocyclyl optionally substituted with 0-6        R^(L1) and/or R^(L2) groups, aryl optionally substituted with        0-6 R^(L1) and/or R^(L2) groups, heteroaryl optionally        substituted with 0-6 R^(L1) and/or R^(L2) groups, where R^(L1)        or R^(L2), each independently are optionally linked to other        groups to form cycloalkyl and/or heterocyclyl moiety, optionally        substituted with 0-4 R^(L5) groups; and    -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈ alkyl, OC₁₋₈ alkyl, SC₁₋₈ alkyl,        NHC₁₋₈ alkyl, N(C1-8alkyl)₂, C3-11cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈cycloalkyl, SC₁₋₈ cycloalkyl, NHC₁₋₈        cycloalkyl, N(C₁₋₈ cycloalkyl)₂, N(C₁₋₈cycloalkyl)(C₁₋₈ alkyl),        OH, NH₂, SH, SO₂C₁₋₈ alkyl, P(O)(OC₁₋₈ alkyl)(C₁₋₈ alkyl),        P(O)(OC₁₋₈ alkyl)₂, CC—C₁₋₈ alkyl, CCH, CH═CH(C₁₋₈ alkyl),        C(C₁₋₈ alkyl)═CH(C₁₋₈ alkyl), C(C₁₋₈ alkyl)═C(C₁₋₈ alkyl)₂,        Si(OH)₃, Si(C₁₋₈ alkyl)₃, Si(OH)(C₁₋₈ alkyl)₂, COC₁₋₈ alkyl,        CO₂H, halogen, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅, SO₂NHC₁₋₈ alkyl,        SO₂N(C1-8alkyl)₂, SONHC₁₋₈ alkyl, SON(C₁₋₈ alkyl)₂, CONHC₁₋₈        alkyl, CON(C₁₋₈ alkyl)₂, N(C₁₋₈alkyl)CONH(C₁₋₈ alkyl), N(C₁₋₈        alkyl)CON(C₁₋₈ alkyl)₂, NHCONH(C₁₋₈ alkyl), NHCON(C₁₋₈ alkyl)₂,        NHCONH₂, N(C₁₋₈ alkyl)SO₂NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)        SO₂N(C₁₋₈alkyl)₂, NH SO₂NH(C₁₋₈ alkyl), NH SO₂N(C₁₋₈ alkyl)₂, NH        SO₂NH₂.

In any aspect or embodiment described herein, the A^(L) is selected fromthe group consisting of:

-   —N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-,-   —O—(CH2)_(m)—O(CH2)_(m)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-,-   —O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;-   —N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;-   —(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;-   —(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—OCH2-;

wherein

-   -   m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3,        4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20;    -   when the number is zero, there is no N—O or O—O bond    -   R of the linker is H, methyl and ethyl;    -   X of the linker is H and F

-   -   where m of the linker can be 2, 3, 4, 5;

-   -   where each n and m of the linker can independently be 0, 1, 2,        3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

In any aspect or embodiment described herein, the A^(L) is selected fromthe group consisting of:

wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

In any aspect or embodiment described herein, the A^(L) is selected fromthe group consisting of:

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In any aspect or embodiment described herein, the A^(L) is selected fromthe group consisting of:

In any aspect or embodiment described herein, the A^(L) is selectedfrom:

wherein:

-   -   ‘X” in above structures can be linear chain with atoms ranging        from 2 to 14, and the mentioned chain can contain heteroatoms        such as oxygen; and    -   “Y” in above structures can be O, N, S(O)_(n) (n=0, 1, 2).

In any aspect or embodiment described herein, the linker (L) comprises astructure selected from:

wherein:

-   -   W^(L1) and W^(L2) are each independently absent, a 4-8 membered        ring with 0-4 heteroatoms, optionally substituted with R^(Q),        each R^(Q) is independently a H, halo, OH, CN, CF₃, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), or 2 R^(Q) groups        taken together with the atom they are attached to, form a 4-8        membered ring system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; or C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or CLM        moieties.

In any aspect or embodiment described herein, the linker comprises astructure selected from:

wherein:

-   -   W^(L1) and W^(L2) are each independently absent, aryl,        heteroaryl, cyclic, heterocyclic, C₁₋₆ alkyl and optionally one        or more C atoms are replaced with O, C₁₋₆ alkene and optionally        one or more C atoms are replaced with O, C1-6 alkyne and        optionally one or more C atoms are replaced with O, bicyclic,        biaryl, biheteroaryl, or biheterocyclic, each optionally        substituted with R^(Q), each R^(Q) is independently a H, halo,        OH, CN, CF₃, hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁-C₆ alkyl (linear, branched, optionally substituted), C₁-C₆        alkoxy (linear, branched, optionally substituted), OC₁₋₃ alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 4-8 membered ring system        containing 0-4 heteroatoms; Y^(L1) is each independently a bond,        NR^(YL1), O, S, NR^(YL2), CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂,        C₁-C₆ alkyl (linear, branched, optionally substituted) and        optionally one or more C atoms are replaced with O; C₁-C₆ alkoxy        (linear, branched, optionally substituted); Q^(L) is a 3-6        membered alicyclic or aromatic ring with 0-4 heteroatoms,        optionally bridged, optionally substituted with 0-6 R^(Q), each        R^(Q) is independently H, C₁₋₆ alkyl (linear, branched,        optionally substituted by 1 or more halo, C₁₋₆ alkoxyl), or 2        R^(Q) groups taken together with the atom they are attached to,        form a 3-8 membered ring system containing 0-2 heteroatoms);    -   R^(YL1), R^(YL2)are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or CLM        moieties.

In any aspect or embodiment described herein, the linker (L) is apolyethylenoxy group optionally substituted with aryl or phenylcomprising from 1 to 10 ethylene glycol units.

In any aspect or embodiment described herein, the PTM is an estrogenreceptor (ER) binding moiety represented by the chemical structure:

wherein:

-   -   X_(PTM) is O or C═O;    -   each of X_(PTM1) and X_(PTM2) is independently selected from N        or CH;    -   R_(PTM1) is independently selected from OH, O(CO)R_(PTM),        O-lower alkyl, wherein R_(PTM) is an alkyl or aryl group in the        ester;    -   R_(PTM2) and R_(PTM4) are independently selected from H, OH,        halogen, CN, CF₃, SO₂-alkyl, 0-lower alkyl;    -   R_(PTM3) and R_(PTM5) are independently selected from H,        halogen;    -   PTM-I has at least one R_(PTM2) and at least one R_(PTM3) on        each respective rings; and    -   the

-   -    indicates the site of attachment of at least one of the linker,        the CLM, a CLM′, or a combination thereof.

In any aspect or embodiment described herein, the PTM is an estrogenreceptor (ER) binding moiety represented by the chemical structure:

wherein:

-   -   each X_(PTM) is independently CH, N;    -   indicates the site of attachment of at least one of the linker        (L), the CLM, a CLM′, ULM, an ILM, a VLM, MLM, a ULM′, a ILM′, a        VLM′, a MLM′, or a combination thereof;    -   each R_(PTM1) is independently OH, halogen, alkoxy, methoxy,        ethoxy, O(CO)R_(PTM), wherein the substitution can be a mono-,        di- or tri-substitution and the R_(PTM) is alkyl or cycloalkyl        group with 1 to 6 carbons or aryl groups;    -   each R_(PTM2) is independently H, halogen, CN, CF₃, liner or        branched alkyl, alkoxy, methoxy, ethoxy, wherein the        substitution can be mono- or di-substitution;    -   each R_(PTM3) is independently H, halogen, wherein the        substitution can be mono- or di-substitution; and    -   R_(PTM4) is a H, alkyl, methyl, ethyl.

In any aspect or embodiment described herein, the PTM is an androgenreceptor (AR) binding moiety (ABM) represented by a structure selectedfrom the group consisting of:

wherein:

-   -   W¹ is aryl, heteroaryl, bicyclic, or biheterocyclic, each        independently substituted by 1 or more H, halo, hydroxyl, nitro,        CN, C≡CH, C₁₋₆ alkyl (linear, branched, optionally substituted;        for example, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), C₁₋₆ alkoxyl (linear, branched, optionally        substituted; for example, optionally substituted by 1 or more        halo), C₂₋₆ alkenyl, C₂₋₆ alkynyl, or CF₃;    -   Y¹, Y² are each independently NR^(Y1), O, S, SO₂, heteroaryl, or        aryl;    -   Y³, Y⁴, Y⁵ are each independently a bond, O, NR^(Y2),        CR^(Y1)R^(Y2), C═O, C═S, SO, SO₂, heteroaryl, or aryl;    -   Q is a 3-6 membered ring with 0-4 heteroatoms, optionally        substituted with 0-6 R^(Q), each R^(Q), is independently H, C₁₋₆        alkyl (linear, branched, optionally substituted, for example,        optionally substituted by 1 or more halo, C₁₋₆ alkoxyl),        halogen, C₁₋₆ alkoxy, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 3-8 membered ring system        containing 0-2 heteroatoms);    -   R¹, R², R^(a), R^(b), R^(Y1), R^(Y2) are each independently H,        C₁₋₆ alkyl (linear, branched, optionally substituted; for        example, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), halogen, C₁₋₆ alkoxy, cyclic, heterocyclic or R¹, R²        together with the atom they are attached to, form a 3-8 membered        ring system containing 0-2 heteroatoms);    -   W² is a bond, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, O, aryl, heteroaryl,        alicyclic, heterocyclic, biheterocyclic, biaryl, or        biheteroaryl, each optionally substituted by 1-10 R^(W2);    -   each R^(W2) is independently H, halo, C₁₋₆ alkyl (linear or        branched optionally substituted; for example, optionally        substituted by 1 or more F), —OR^(W2A), C₃₋₆ cycloalkyl, C₄₋₆        cycloheteroalkyl, C₁₋₆ alkyl (optionally substituted),        heterocyclic (optionally substituted), aryl (optionally        substituted), or heteroaryl (optionally substituted), bicyclic        heteroaryl or aryl, OC₁₋₃ alkyl (optionally substituted; for        example, optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN;    -   R^(W2A) is H, C₁₋₆ alkyl (linear, branched), or C₁₋₆ heteroalkyl        (linear, branched), each optionally substituted by a cycloalkyl,        cycloheteroalkyl, aryl, heterocyclic, heteroaryl, halo, or        OC₁₋₃alkyl; and    -   the dashed line indicates the site of attachment of at least one        of the linker, the CLM, a CLM′, or a combination thereof.

In any aspect or embodiment described herein, the PTM is a BET/BRD4targeting moiety comprising a group according to the chemical structurePTM-a:

wherein:

-   -   Y₁, Y₂ and Y₃ are independently selected from the group of        carbon, nitrogen or oxygen and together with the atoms to form        an aromatic fused ring.    -   A and B are independently selected from the group of a        5-membered aromatic ring, a 6-membered aromatic ring, a        heteroaromatic ring, a carbocyclic, a thiophene a pyrrole ring,        a pyridine, a pyrimidine, a pyrazine, a pyrazole ring each        optionally substituted with alkyl, alkoxy, halogen, an aromatic        and a heteroaromatic ring; wherein ring A is fused to the        central azepine (Y1=C) or diazepine (Y1=N) moiety; and    -   Z1 is selected from the group of methyl or an alkyl group, and    -   wherein the dashed line indicates the site of attachment of at        least one of the linker, the CLM, a CLM′, or a combination        thereof.

In any aspect or embodiment described herein, the PTM is a BRaftargeting moiety that is represented by at least one of chemicalstructures PTM-Ia, PTM-Ib, PTM-IIa, PTM-IIb, PTM-IIIa, PTM-IIIb,PTM-IVa, PTM-IVb:

wherein:

-   -   double dotted bonds are aromatic bonds;    -   V_(PTM), W_(PTM), X_(PTM), Y_(PTM), Z_(PTM) is one of the        following combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C,        CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N,        CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH,        C, N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C; and C,        N, N, N, C;    -   R_(PTM1) is covalently joined to a ULM, a chemical linker group        (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a VLM′,        a MLM′, or combination thereof;    -   R_(PTM2) is hydrogen, halogen, aryl, methyl, ethyl, OCH₃, NHCH₃        or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM3) is absent, hydrogen, aryl, methyl, ethyl, other alkyl,        cyclic alkyl, OCH₃, NHCH₃ or Ml-CH₂—CH₂-M2, wherein M1 is CH₂, O        and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or        heterocycle;    -   R_(PTM4) is hydrogen, halogen, aryl, methyl, ethyl, OCH₃, NHCH₃        or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   each of R_(PTM5) and R_(PTM22) is independently selected from        the group consisting of

-   -   X_(PTM1), X_(PTM2), X_(PTM3), X_(PTM4), X_(PTM5), X_(PTM6),        X_(PTM7), X_(PTM8), X_(PTM9), X_(PTM10), X_(PTM11), X_(PTM12),        X_(PTM13), X_(PTM14), X_(PTM15), X_(PTM16), X_(PTM17),        X_(PTM18), X_(PTM19), X_(PTM20), X_(PTM21), X_(PTM22),        X_(PTM23), X_(PTM24), X_(PTM25), X_(PTM26), X_(PTM27),        X_(PTM28), X_(PTM29), X_(PTM30), X_(PTM31), X_(PTM32),        X_(PTM33), X_(PTM34), X_(PTM35), X_(PTM36), X_(PTM37), X_(PTM38)        are independently selected from CH or N;    -   R_(PTM5)a is selected from the group consisting of: H,        optionally substituted amide (e.g., optionally substituted with        an alkyl, methyl, ethyl, propyl, or butyl group), optionally        substituted amine,

-   -    —NHC(O)R_(PTM5);    -   R_(PTM6a) and R_(PTM6b) are each independently selected from        hydrogen, halogen, or C₁-C₆ alkyl (linear, branched, optionally        substituted);    -   R_(PTM6) is either of the following groups: absent, hydrogen,        halogen, aryl, methyl, ethyl, OCH₃, NHCH₃ or M1-CH₂—CH₂-M2,        wherein M1 is CH₂, O and NH, and M2 is hydrogen, alkyl, cyclic        alkyl, aryl or heterocycle.    -   R_(PTM7) is absent, hydrogen, halogen, aryl, methyl, ethyl,        OCH₃, NHCH₃ or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and        M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle.    -   R_(PTM8), R_(PTM9) or R_(PTM10) are independently selected from        the group consisting of absent, hydrogen, halogen, aryl,        heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH₃,        NHCH₃ or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM11) is absent, hydrogen, halogen, methyl, ethyl, OCH₃,        NHCH₃ or M1-CH₂—CH₂-M2 in which M1, wherein CH₂, O and NH, and        M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM12), R_(PTM13), R_(PTM14), R_(PTM15), R_(PTM16),        R_(PTM17), R_(PTM18), R_(PTM19) are independently selected from        the group consisting of absent, hydrogen, halogen, aryl,        heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl,        OCH₃, NHCH₃ or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O and NH, and        M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM20) is a small group containing less than four        non-hydrogen atoms;    -   R_(PTM2)i is selected from the group consisting of        trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl,        isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, OCH₃, NHCH₃, dimethylamino        or M1-CH₂—CH₂-M2, wherein M1 is CH₂, O or NH, and M2 is        hydrogen, alkyl, cyclic alkyl, aryl or heterocycle;    -   R_(PTM25a) and R_(PTM25b) are each independently selected from        hydrogen, halogen, or C₁-C₆ alkyl (linear, branched, optionally        substituted);    -   R_(PTM23), R_(PTM24), R_(PTM28), R_(PTM29), R_(PTM30),        R_(PTM31), R_(PTM32) are independently selected from the group        consisting of absent, bond, hydrogen, halogen, aryl (optionally        substituted), heteroaryl (optionally substituted), cycloalkyl        (optionally substituted), heterocycle (optionally substituted),        methyl, ethyl (optionally substituted), other alkyl (linear,        branched, optionally substituted), OCH₃, NHCH₃ or M1-CH₂—CH₂-M2,        wherein M1 is CH₂, O and NH, and M2 is hydrogen, alkyl (linear,        branched, optionally substituted), cyclic alkyl (optionally        substituted), aryl (optionally substituted) or heterocycle        (optionally substituted);    -   R_(PTM25) is selected from absent, hydrogen, halogen, C₁-C₆        alkyl (linear, branched, optionally substituted), OCH₃, NHCH₃ or        SCH₃;    -   R_(PTM26) is selected from absent, hydrogen, halogen, C₁-C₆        alkyl (linear, branched, optionally substituted), OCH₃, NHCH₃ or        SCH₃;    -   R_(PTM27) is selected from the group consisting of absent,        hydrogen, halogen, C₁-C₆ alkyl (linear, branched, optionally        substituted), OCH₃, NHCH₃ or SCH₃; and    -   at least one of R_(PTM8), R_(PTM9) or R_(PTM10), R_(PTM12),        R_(PTM13), R_(PTM16), R_(PTM24), R_(PTM29), and R_(PTM32) is        modified to be covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, when R_(PTM9) is thecovalently joined position, R_(PTM7) and R_(PTM8) are connected togethervia a covalent bond in a way to form a bicyclic group with the ring towhich R_(PTM7) and R_(PTM8) are attached.

In any aspect or embodiment described herein, when R_(PTM8) is thecovalently joined position, R_(PTM9) and R_(PTM10) are connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM9) and R_(PTM10) are attached.

In any aspect or embodiment described herein, when R_(PTM10) is thecovalently joined position, R_(PTM8) and R_(PTM9) are connected togethervia a covalent bond in a way to form a bicyclic group with the ring towhich R_(PTM8) and R_(PTM9) are attached.

In any aspect or embodiment described herein, when R_(PTM12) is thecovalently joined position, R_(PTM13) and R_(PTM14) are connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM13) and R_(PTM14) are attached, and/or R_(PTM15) andR_(PTM16) are connected together via a covalent bond in a way to form abicyclic group with the ring to which R_(PTM15) and R_(PTM16) areattached.

In any aspect or embodiment described herein, when R_(PTM13) is thecovalently joined position, R_(PTM12) and R_(PTM16) are connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM12) and R_(PTM16) are attached, and/or R_(PTM15) andR_(PTM16) are connected together via a covalent bond in a way to form abicyclic group with the ring to which R_(PTM15) and R_(PTM16) areattached.

In any aspect or embodiment described herein, when R_(PTM16) is thecovalently joined position, R_(PTM12) and R_(PTM13) are connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM12) and R_(PTM13) are attached, and/or R_(PTM13) andR_(PTM14) are connected together via a covalent bond in a way to form abicyclic group with the ring to which R_(PTM13) and R_(PTM14) areattached.

In any aspect or embodiment described herein, when R_(PTM24) is thecovalently joined position, R_(PTM31) and R_(PTM32) are connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM31) and R_(PTM32) are attached, or R_(PTM29) andR_(PTM30) are connected together via a covalent bond in a way to form abicyclic group with the ring to which R_(PTM29) and R_(PTM30) areattached.

In any aspect or embodiment described herein, when R_(PTM29) is thecovalently joined position, R_(PTM24) and R_(PTM32) are connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM24) and R_(PTM32) are attached, and/or R_(PTM31) andR_(PTM32) are connected together via a covalent bond in a way to form abicyclic group with the ring to which R_(PTM31) and R_(PTM32) areattached.

In any aspect or embodiment described herein, when R_(PTM32) is thecovalently joined position, R_(PTM24) and R_(PTM29) are connectedtogether via a covalent bond in a way to form a bicyclic group with thering to which R_(PTM24) and R_(PTM29) are attached, and/or R_(PTM29) andR_(PTM30) are connected together via a covalent bond in a way to form abicyclic group with the ring to which R_(PTM29) and R_(PTM30) areattached.

In any aspect or embodiment described herein, the PTM has a structureselected from the group consisting of:

wherein:

-   -   R is H, a lower alkyl, a bond, or a chemical moiety coupling the        CLM to the PTM; and    -   Linker is a bond or a chemical linker moiety coupling the CLM to        the PTM, including pharmaceutically acceptable salt forms        thereof.

In any aspect or embodiment described herein, the compound is selectedfrom the group consisting of compounds 1-52.

A further aspect of the present disclosure provides a compositioncomprising an effective amount of a bifunctional compound of the presentdisclosure, and a pharmaceutically acceptable carrier.

In any aspect or embodiment described herein, the composition furthercomprises at least one of additional bioactive agent or anotherbifunctional compound of the present disclosure.

In any aspect or embodiment described herein, the additional bioactiveagent is anti-cancer agent, an anti-neurodegenerative agent, anantimicrobial agent, an antiviral agent, an anti-HIV agent, or anantifungal agent.

An additional aspect of the present disclosure provides a compositioncomprising an effective amount of at least one compound of the presentdisclosure and a pharmaceutically acceptable carrier, additive, and/orexcipient for treating a disease or disorder in a subject, the methodcomprising administering the composition to a subject in need thereof,wherein the compound is effective in treating or ameliorating at leastone symptom of the disease or disorder.

In any aspect or embodiment described herein, the disease or disorder isassociated with the accumulation and/or aggregation of the targetprotein.

In any aspect or embodiment described herein, the disease or disorder isselected from the group consisting of asthma, autoimmune diseases suchas multiple sclerosis, various cancers, ciliopathies, cleft palate,diabetes, heart disease, hypertension, inflammatory bowel disease,mental retardation, mood disorder, obesity, refractive error,infertility, Angelman syndrome, Canavan disease, Coeliac disease,Charcot-Marie-Tooth disease, Cystic fibrosis, Duchenne musculardystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome,Neurofibromatosis, Phenylketonuria, Polycystic kidney disease, (PKD1) or4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease,Turner syndrome.

In any aspect or embodiment described herein, the disease or disorder isselected from the group consisting of Alzheimer's disease, Amyotrophiclateral sclerosis (Lou Gehrig's disease), Anorexia nervosa, Anxietydisorder, Atherosclerosis, Attention deficit hyperactivity disorder,Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructivepulmonary disease, Crohn's disease, Coronary heart disease, Dementia,Depression, Diabetes mellitus type 1, Diabetes mellitus type 2,Epilepsy, Guillain-Barré syndrome, Irritable bowel syndrome, Lupus,Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke,Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

In any aspect or embodiment described herein, the disease or disorder isselected from the group consisting of aceruloplasminemia,Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher diseasetype 2, acute intermittent porphyria, Canavan disease, AdenomatousPolyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyasedeficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-Dporphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease,Alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha-1proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alströmsyndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratasedeficiency, Anderson-Fabry disease, androgen insensitivity syndrome,Anemia Angiokeratoma Corporis Diffusum, Angiomatosis retinae (vonHippel-Lindau disease) Apert syndrome, Arachnodactyly (Marfan syndrome),Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlossyndrome # arthrochalasia type) ataxia telangiectasia, Rett syndrome,primary pulmonary hypertension, Sandhoff disease, neurofibromatosis typeII, Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,familial, Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dube syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Kennedy's syndrome,Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome,Jackson-Weiss syndrome, Kidney diseases, including hyperoxaluria,Klinefelter's syndrome, Kniest dysplasia, Lacunar dementia,Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies), TreacherCollins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease),Vision impairment and blindness (Alström syndrome), Vrolik disease,Waardenburg syndrome, Warburg Sjo Fledelius Syndrome,Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, WolffPeriodic disease, Weissenbacher-Zweymüller syndrome and Xerodermapigmentosum.

In any aspect or embodiment described herein, the composition furthercomprises an additional bioactive agent.

In any aspect or embodiment described herein, the additional bioactiveagent is at least one of an anti-cancer agent, an anti-neurodegenerativeagent, an antimicrobial agent, an antiviral agent, an anti-HIV agent, anantifungal agent, or a combination thereof.

In any aspect or embodiment described herein, the anticancer agent isselected from the group consisting of everolimus, trabectedin, abraxane,TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin,vandetanib, ARQ-197, MK-0457, MLN₈O₅₄, PHA-739358, R-763, AT-9263, aFLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurorakinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDACinhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFRTK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinaseinhibitors, an AKT inhibitor, an mTORC1/2 inhibitor, a JAK/STATinhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinaseinhibitor, a Map kinase (mek) inhibitor, a VEGF trap antibody,pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab,amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin,ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan,tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111,131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan,IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402, lucanthone, LY 317615,neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311,romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat,etoposide, gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258,);3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib,AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH 2 acetate[C₅₉H₈₄N₁₈Oi₄-(C₂H₄O₂)x where x=1 to 2.4], goserelin acetate, leuprolideacetate, triptorelin pamoate, medroxyprogesterone acetate,hydroxyprogesterone caproate, megestrol acetate, raloxifene,bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;TAK-165, HKI-272, erlotinib, lapatanib, canertinib, AB X-EGF antibody,erbitux, EKB -569, PKI-166, GW-572016, Ionafarnib, BMS-214662,tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid,valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951,aminoglutethimide, amsacrine, anagrelide, L-asparaginase, BacillusCalmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin,busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine,clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin,daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevac, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor -freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonists,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

An additional aspect of the present disclosure provides a method forinducing degradation of a target protein in a cell comprisingadministering an effective amount of a compound of the presentdisclosure to the cell, wherein the compound effectuates degradation ofthe target protein.

Another aspect of the present disclosure provides a compositioncomprising an effective amount of a compound of the present disclosurefor use in a method for treating cancer, said method comprisingadministering the composition to a patient in need thereof, wherein thecomposition is effectuates for the treatment or alleviation of at leastone symptom of cancer in the patient.

In any aspect or embodiment described herein, the cancer issquamous-cell carcinoma, basal cell carcinoma, adenocarcinoma,hepatocellular carcinomas, and renal cell carcinomas, cancer of thebladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver,lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benignand malignant lymphomas, particularly Burkitt's lymphoma andNon-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; multiple myeloma, sarcomas, includingEwing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma,myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas,astrocytomas, oligodendrogliomas, ependymomas, gliobastomas,neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas,pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, andSchwannomas; bowel cancer, breast cancer, prostate cancer, cervicalcancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer,thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer,stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma,Hodgkin's disease, Wilms' tumor or teratocarcinomas, T-lineage Acutelymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL),Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-BLymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL,Philadelphia chromosome positive ALL and Philadelphia chromosomepositive CML.

While preferred embodiments of the invention have been shown anddescribed herein, it will be understood that such embodiments areprovided by way of example only. Numerous variations, changes andsubstitutions will occur to those skilled in the art without departingfrom the spirit of the invention. Accordingly, it is intended that theappended claims cover all such variations as fall within the spirit andscope of the invention.

Examples

A. Protein Degradation Bioassays:

The following bioassays evaluate the level of protein degradationobserved in various cell types using representative compounds disclosedherein.

In each bioassay, cells were treated with varying amounts of compoundsencompassed by the present disclosure. The degradation of the followingproteins may be evaluated: estrogen receptor α (ERα),bromodomain-containing protein 4 (BRD4), androgen receptor (AR), andBRaf protein.

1. ERE Luciferase Assay for Compounds in Table 5.

T47D-KBluc cells (ATCC® # CRL_2865, T47D human breast cancer cellsstably transfected with estrogen responsive element/promoter/luciferasereporter gene) were seeded into 96-well white opaque plates in RPMIgrowth medium supplemented with 10% fetal bovine serum (FBS) and allowedto adhere overnight in a 37° C. humidified incubator. The following day,cells were treated with PROTACs in a 12-point concentration curve (topfinal concentration of 300 nM with subsequent concentrations being3-fold less with 2 pM being the lowest concentration in the assay). EachPROTAC was tested independently in two experiments on 96-well plates.After 24 hours, media was removed and lysis buffer was added to thewells. Following lysis, Bright-Glom′ Luciferase Assay Substrate(Promega, Madison Wis.) was added and the luciferase activity wasmeasured using a Cytation 3 plate reader (BioTek™, Winooski, Vt.). Eachcompound was assayed in duplicate and the activity was calculated asIC50 using GraphPad Prism software (San Diego, Calif.).

2. Estrogen Receptor -Alpha (ERα) Degradation Assay in MCF-7 Cells UsingWestern Blot Method for Table 5.

The exemplary novel ERα degraders were assessed for their activity indegrading ERα in MCF-7 cells via western blot. The assay was carried outin the presence of 10% FBS or high percentage of human or mouse serum.Protocols of the western blot assay are described below.

MCF7 cells were grown in DMEM/F12 with 10% PBS and seeded at 24,000cells per well in 100 μl into 96-well clear tissue culture plates. Thefollowing day, the cells were treated with PROTACs in a 7-pointconcentration curve with 100 nM being the top concentration and serialdilutions to make the other concentrations (30 nM, 1.0 nM, 3 nM, 1 nM,and 0.3 nM). At all concentrations, 0.01% DMSO is the finalconcentration in the well. The following day, the plates are aspirated,washed with 50 μl of cold PBS. The cells are lysed with 50 μl/well 4° C.Cell Lysis Buffer (Catalog #9803; Cell Signaling Technology, Danvers,Mass.) (20 mM Tris-HCL (pH 7.5), 150 mM NaCl, 1 mM Na₂EDTA, 1 mM EGTA,1% Triton, 2.5 mM sodium pyrophosphate, 1 mM B-glycerophosphate, 1 mMsodium vanadate, 1 ug/ml leupeptin). Lysates were clarified at 16,000×gfor 10 minutes, and 2 μg of protein was subjected to SDS-PAGE analysisand followed by immunoblotting according to standard protocols. Theantibodies used were ERα (Cell Signaling Technologies Catalog #8644),and Tubulin (Sigma Catalog # T9026; St. Louis, Mo.). Detection reagentswere Clarity Western ECL substrate (Bio-Rad Catalog #170-5060; Hercules,Calif.).

Alternatively, MCF7 cells were grown in DMEM/F12 with 10% FBS and seededat 24,000 cells per well in 500 μl in 24-well clear tissue cultureplates. The following day, the cells were treated with PROTACs in a5-point concentration curve (100 nM, 33 nM, 11 nM, 3.7 nM, and 1.2 nM)in the presence of 0.01% DMSO. After 72 hours, the wells are aspiratedand washed with 500 μl of PBS. The cells are lysed with 100 μl/well 4°C. Cell Lysis Buffer (Catalog #9803; Cell Signaling Technology, Danvers,Mass.) (20 mM Tris-HCL (pH 7.5), 150 NaCl, 1 mM Na₂EDTA, 1 mM EGTA. 1%Triton, 2.5 mM sodium pyrophosphate, 1 mM B-glycerophosphate, 1 mMsodium vanadate, 1 ug/ml leupeptin). Lysates were clarified at 16,000×gfor 10 minutes, and 2 ug of protein was subjected to SDS-PAGE analysisand followed by immunoblotting according to standard protocols. Theantibodies used were ERα (Cell Signaling Technologies Catalog #8644),and Tubulin (Sigma Catalog # T9026; St. Louis, Mo.). Detection reagentswere Clarity Western ECL substrate (Bio-Rad Catalog #170-5060; Hercules,Calif.).

3. Estrogen Receptor -Alpha (ERα) Degradation Assay Using in-CellWestern™ Assay for Table 5.

Degradation of ERα by claimed compounds were determined in MCF7 cellsusing an In-Cell Western™ assay. Briefly, MCF7 cells were plated in96-well plates (2000 cells per well in 100 μl media) and incubated at37° C. under an atmosphere of 5% CO₂ in a humidified incubatorovernight. One-hundred (100) μl of media containing test compound (at 2xconcentration) was added to the appropriate wells to provide 11 seriallydecreasing concentrations (top final concentration, 1 μM then 3-foldless for the next 10 concentrations); a vehicle control (DMSO) was alsoadded for each compound. For each experiment, all compounds were assayedin duplicate plates. Cells were then incubated for 3 or 5 days in theabove-mentioned environment. The assay was terminated by removal ofmedia, a single wash with ice-cold PBS and the addition of 50 μlparaformaldehyde (PFA: 4% in PBS). After 15 minutes in PFA at roomtemperature, the cells were permeabilized in Tris-phosphate-bufferedsaline with Tween (0.1%) (TBST) supplemented with Triton X-100 (0.5%)for 15 minutes. Cells were then blocked in BSA (TBST with BSA, 3%) forone hour. Primary antibodies for the detection of ERα (rabbitmonoclonal, 1:1000, Cell Signaling Technology Catalog #8644) and tubulin(mouse monoclonal, 1:5000, Sigma Catalog # T6074) in TBST with BSA (3%)were added. The cells were incubated overnight at 4° C. The cells werethen washed thrice with TBST at room temperature and then incubated withanti-rabbit and anti-mouse fluorescently-labelled secondary antibodies(IRDye®; LI-COR; Lincoln, Nebr.) in LI-COR blocking buffer (Catalog#927-50000) for one hour at room temperature. Following 3 washes withTBST, the buffer was removed and the plates were read on an Odyssey®infrared imaging system (LI-COR®; Lincoln, Nebr.) at 700 nm and 800 nm.Using commercial software (ImageStudio™; LI-COR, Lincoln, Nebr.), thestaining intensity for ERα and tubulin in each well was quantified andexported for analysis. For each data point, ERα intensity was normalizedto tubulin intensity and for each compound all normalized intensityvalues were normalized to the vehicle control. DC₅₀ and D_(max) valueswere determined following a 4-parameter IC₅₀ curve fit using ACAS doseresponse module (McNeil & Co Inc.).

4. AR ELISA Assay Protocol for Table 6

Compounds were evaluated in this assay in LNCaP and/or VCaP cellsutilizing similar protocols. The protocols used with VCaP cells aredescribed below. The androgen receptor ELISA assay was performed usingPathScan AR Sandwich ELISA (Cell Signaling Catalog #12850) according tothe following assay steps:

VCaP cells were seeded at 40,000 cells/well at a volume of 100 μL/wellin VCaP assay medium [Phenol red free RPMI (Gibco Cat #11835-030); 5%Charcoal Stripped (Dextran treated) FBS (Omega Scientific, Cat # FB-04);1% penstrep (Life Technologies, Gibco Cat #: 10378-016)] in Corning 3904plates. The cells were incubated for a minimum of 3 days. Cells weredosed with PROTACs diluted in 0.01% DMSO and the drug treatment wasallowed for 5 hours.

AR ELISA (Cell Signaling) was performed as follows. 1× Cell SignalingCell lysis buffer was made (Catalogue #9803; comes with the kit). Mediafrom the treated wells is aspirated, and 100 μL 1× cell lysisbuffer/well is added. The cells were placed on a shaker for 10 minutesat 4° C. Twenty microliters of lysate was transferred to 100 μl ofDiluent in ELISA plate (0.15m/ml-0.075 μg/ml). The lysate-diluentmixture was shaken for 30 minutes at 37° C. Allow mouse AR antibody,anti-mouse antibody, TMB, and STOP solution to come to room temperature.The 1× ELISA buffer included in kit was made and loaded in thereservoir. Media from the plates was discarded, the ELISA plate tappedhard on paper towel, and washed 4×200 μl ELISA wash buffer using a platewasher.

One-hundred (100) μL/well of mouse AR detection Ab was added; the plateswere covered and shaken at 37° C. for 1 hour; media was discarded fromthe plates, the plates were tapped on a paper towel, washed 4× with 200μL ELISA wash buffer with a plate washer.

One-hundred (100) μL/well of anti-mouse-HRP conjugated Ab (comes withthe kit) was added; the plates were covered and shaken at 37° C. for 30minutes; the TMB reagent was allowed to come to room temperature; themedia was discard from the plate, the plates were tapped on paper towel,washed 4x with 200 μL of ELISA wash buffer; the plates were tapped theplates on paper towel. One-hundred (100) μL of TMB was added and theplates shaken for 2 minutes—while watching for color development.One-hundred (100) μL Stop solution was added when light blue colordeveloped. Plates were shaken and read at 450 nM.

Progression of prostate cancer in patients treated with anti-androgentherapy usually involves one of several mechanisms of enhanced AndrogenReceptor (AR) signaling, including increased intratumoral androgensynthesis, increased AR expression and AR mutations. PROTACs(PROteolysis TArgeting Chimera), which use bi-functional molecules thatsimultaneously bind a target of choice and an E3 ligase, causeubiquitination via induced proximity and degradation of the targeted,pathological protein. As opposed to traditional target inhibition, whichis a competitive process, degradation is a progressive process. As such,it is less susceptible to increases in endogenous ligand, targetexpression, or mutations in the target. Thus, this technology appears tobe ideal for addressing the mechanisms of AR resistance in patients withprostate cancer. Data was analyzed and plotted using GraphPad Prismsoftware.

5. BRaf Protein In Vitro Degradation Assay (A375 Cells) of Table 7

A375 cells were cultured in ATCC DMEM+10% FBS in 12 well plates, andtreated with indicated compound from Tables 1-41 or 0.1% DMSO vehiclecontrol for 16 hours. Cells were harvested in Cell Signaling lysisbuffer (Cat #9803) with the addition of Roche protease inhibitor tablets(Cat #11873580001), and lysates clarified by microcentrifugation.Proteins were separated by SDS-PAGE, and transferred onto nitrocellulosemembranes using an Invitrogen iBlot system. Immunoblotting was performedfor BRaf (Santa Cruz Cat #9002), CRAF (BD Cat #610151), and pErk (CellSignaling Cat #9106). GAPDH (Cell Signaling Cat #2118) was used as aloading control. Quantification was carried out using the BioRad ImageLab 5 software.

6. BRaf in-Cell Western Cellular Degradation Assay (A375 Cells) of Table7

A375 cells were cultured in ATCC DMEM+10% FBS in 96-well plates, andtreated with indicated compounds from Tables-43 or 0.1% DMSO vehiclecontrol for 72 hours. Cells were washed with PBS 1×, and affixed toplate using 4% PFA in phosphate buffered saline for 15 minutes; washed1× and permeabilized using 0.1% Triton-X-100 in PBS for 5 minutes;washed 1× and blocked with LICOR blocker (Cat. #927-50000) for 1 hour.Cells were then incubated with B-Raf antibody (Santa Cruz Cat #9002,Santa Cruz Cat #528) and tubulin antibody (Sigma # T6074) in LICORblocker for 18 hours. Cells were washed 3x prior to adding secondaryantibodies (LICOR cat #926-32210 and 926-68071) and incubated for 1hour. Cells were washed 3x and imaged using LICOR Odyssey Software.

7. BRD4 Western Protocol for Table 8

22Rv-1 or VCaP cells were purchased from ATCC and cultured in Dulbecco'sModified Eagle's Medium (ATCC), supplemented with 10% FBS (ATCC) andPenicillin/Streptomycin (Life Technologies). DMSO control and compoundtreatments (0.003 μM, 0.01 μM, 0.03 μM and 0.1 μM) were performed in12-well plates for 16 hours. Cells were harvested, and lysed in RIPAbuffer (50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodiumdeoxycholate) supplemented with protease and phosphatase inhibitors.Lysates were clarified at 16,000 g for 10 minutes, and proteinconcentration was determined. Equal amount of protein (20 μg) wassubjected to SDS-PAGE analysis and followed by immunoblotting accordingto standard protocols. The antibodies used were BRD4 (Cell Signaling#13440), and Actin (Sigma #5441). Detection reagents were ClarityWestern ECL substrate (Bio-rad #170-5060).

TABLE 1 Exemplary Estrogen Receptor PROTACs General Ex. Synthetic #Chemical Structure Name Method 1

3-{5-[4-(5-{4-[(1S,2R)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl]phenoxy}pentyl)piperazin-1-yl]-7-methoxy-1-oxo-2,3- dihydro-1H-isoindol-2-yl}piperidine-2,6-dione A-2, A-8 2

3-(5-(4-(5-(4-((1R, 2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenoxy)pentyl)piperazin- 1-yl)-7-methoxy-1-oxoisoindolin-2- yl)piperidine-2,6-dione A-2, A-8 Exp. Procedureincluded 3

3-[5-[4-[5-[4-[(1R,2S)-6- hydroxy-2-phenyl-tetralin-1- yl]phenoxy]pentyl]piperazin-1- yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-4, A-8 Exp. Procedure included 4

3-[5-[4-[5-[4-[(1R,2S)-6- hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin- 1-yl]-4-[2-(2- methoxyethoxy)ethoxy]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-4, A-5, A-8 5

3-(5-{4-[(1-{4-[(1S,2R)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}-4- [2-(2- methoxyethoxy)ethoxy]-1-oxo-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6- dione A-4, A-5, A- 126

3-(5-{4-[(1-{4-[(1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}-4- [2-(2- methoxyethoxy)ethoxy]-1-oxo-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6- dione A-4, A-5, A- 127

(3S)-3-(5-{2-[4-(4-{4- [(1S,2R)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1- yl]phenoxy}butyl)-1,4-diazepan-1-yl]ethyl}-4-[2-(2- methoxyethoxy)ethoxy]-1-oxo-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6- dione A-5, A-9 8

(3S)-3-[5-[2-[4-[4-[4- [(1R,2S)-6-hydroxy-2- phenyl-tetralin-1-yl]phenoxy]butyl]-1,4- diazepan-1-yl]ethyl]-4-[2-(2-methoxyethoxy)ethoxy]-1- oxo-isoindolin-2- yl]piperidine-2,6-dione A-5,A-9 9

3-(5-{4-[2-(1-{4-[(1S,2R)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl]phenyl}piperidin-4-yl)ethyl]piperazin-1-yl}-7- methoxy-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine- 2,6-dione A-2, A-13 10

3-[5-[4-[2-[1-[4-[(1R,2S)-6- hydroxy-2-phenyl-tetralin-1- yl]phenyl]-4-piperidyl]ethyl]piperazin-1- yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-2, A-13 11

3-[5-[4-[[1-[4-[(1R,2S)-6- hydroxy-2-phenyl-tetralin-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1- yl]-4-(2-methoxyethoxy)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-4, A-12 12

3-[5-[4-[4,4-difluoro-5-[4- [(1R,2S)-6-hydroxy-2- phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin- 1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-2, A-10 13

(3R)-3-[5-[4-[5-[4-[(1R,2S)- 6-hydroxy-2-phenyl-tetralin- 1-yl]phenoxy]pentyl]piperazin- 1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-2, A-8 14

(3S)-3-[5-[4-[5-[4-[(1R,2S)- 6-hydroxy-2-phenyl-tetralin- 1-yl]phenoxy]pentyl]piperazin- 1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-2, A-8 15

3-[5-[4-[[1-[4-[(1R,2S)-6- hydroxy-2-phenyl-tetralin-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1- yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-2, A-12 16

3-[5-[4-[5-[4-[(1R,2S)-2-(4- fluorophenyl)-6-hydroxy-tetralin-1-yl]phenoxy]- 1,2,3,3a,4,5,6,6a- octahydropentalen-2-yl]piperazin-1-yl]-7- methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione A-2, A-11 17

3-[5-[4-[[6-[[4-[(1R,2S)-6- hydroxy-2-phenyl-tetralin-1-yl]phenoxy]methyl]-2- pyridyl]methyl]piperazin-1- yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-16 18

3-(5-{4-[(1-{2,6-difluoro-4- [(1S,2R)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1- yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}-7- methoxy-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine- 2,6-dione A-1, A-2 19

3-(5-(4-((1-(2,6-difluoro-4- ((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-7- methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione A-1, A-2, A-8 20

3-[7-(difluoromethoxy)-5-[4- [5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1- yl]phenoxy]pentyl]piperazin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-3, A-8 21

3-[5-[4-[4,4-difluoro-5-[4- [(1R,2S)-6-hydroxy-2- phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin- 1-yl]-7-(difluoromethoxy)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-6, A-10 22

3-[7-(difluoromethoxy)-5-[4- [2-[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1- yl]phenyl]-4- piperidyl]ethyl]piperazin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-2, A-13 23

3-[7-(difluoromethoxy)-5-[4- [2-[3-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1- yl]phenoxy]cyclobutyl]ethyl] piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione A-3, A-14 24

3-[5-[4-[2-[1-[2-fluoro-4- [(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]- 4-piperidyl]ethyl]piperazin-1-yl]-7-methoxy-1-oxo- isoindolin-2-yl]piperidine- 2,6-dione A-2, A-1225

3-{7-[4-(5-{4-[(1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl]phenoxy}pentyl)piperazin- 1-yl]-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin- 2-yl}piperidine-2,6-dione A-7, A-8 26

3-[5-[4-[2-[3-[4-[(1R,2S)-6- hydroxy-2-phenyl-tetralin-1-yl]phenoxy]cyclobutyl]-2- oxo-ethyl]piperazin-1-yl]-7-methoxy-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-17 27

3-[7-(difluoromethoxy)-5-[4- [2-[1-hydroxy-3-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin- 1- yl]phenoxy]cyclobutyl]ethyl]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine- 2,6-dione A-3, A-1528

3-[5-[4-[2-[1-hydroxy-3-[4- [(1R,2S)-6-hydroxy-2- phenyl-tetralin-1-yl]phenoxy]cyclobutyl]ethyl] piperazin-1-yl]-7-methoxy-1-oxo-isoindolin-2- yl]piperidine-2,6-dione A-2, A-15 29

3-(6′-{4-[(1-{4-[(1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl]phenyl}piperidin-4-yl)methyl]piperazin-1-yl}-3′- oxo-2′,3′-dihydrospiro[cyclopropane-1,1′-isoindole]-2′- yl)piperidine-2,6-dioneA-6, A-12 30

4-[6′-[4-[[1-[2-fluoro-4- [(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]- 4-piperidyl]methyl]piperazin-1-yl]-3′-oxo-spiro [cyclopropane-1,1′- isoindoline]-2′-yl]piperidine-2,6-dione A-6, A-12 31

A-1, A-2

TABLE 2 Exemplary Androgen Receptor PROTACs Ex. General # ChemicalStructure Name scheme 32

rac-N-((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6- dioxopiperidin-3-yl)-7- methoxy-1,3-dioxoisoindolin-5- yl)piperazin-1- yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide Exp. procedure provided 33

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4- ((4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3- dioxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidin-1- yl)pyrimidine-5- carboxamide B-1, B-2 34

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- ((4-(2′-(2,6-dioxopiperidin- 3-yl)-3′-oxospiro[cyclopropane-1,1′- isoindolin]-6′-yl)piperazin-1-yl)methyl)piperidin-1- yl)benzamide Synthesis described in detail 35

rac-N-((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-5-(4-((((1r,3r)-3-((2′-(2,6- dioxopiperidin-3-yl)-3′-oxospiro[cyclopropane-1,1′- isoindolin]-5′-yl)oxy)cyclobutyl)(isopropyl) amino)methyl)piperidin-1-yl)pyrazine-2-carboxamide Synthesized following the route described forEx. Comp. 34 36

rac-N-((1r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-5-(4-((((1r,3r)-3-((2′-(2,6- dioxopiperidin-3-yl)-3′-oxospiro[cyclopropane-1,1′- isoindolin]-6′-yl)oxy)cyclobutyl)(isopropyl) amino)methyl)piperidin-1-yl)pyrazine-2-carboxamide Synthesized following the route described forEx. Comp. 34 37

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4- ((((1r,3r)-3-((2′-(2,6-dioxopiperidin-3-yl)-3′- oxospiro[cyclopropane-1,1′- isoindolin]-5′-yl)oxy)cyclobutyl)(isopropyl) amino)methyl)piperidin-1-yl)pyrazine-2-carboxamide Synthesized following the route described forEx. Comp. 34 38

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4- ((((1r,3r)-3-((2′-(2,6-dioxopiperidin-3-yl)-3′- oxospiro[cyclopropane-1,1′- isoindolin]-6′-yl)oxy)cyclobutyl)(isopropyl) amino)methyl)piperidin-1-yl)pyrazine-2-carboxamide Synthesized following the route described forEx. Comp. 34 46

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- (5-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4- tetrahydroisoquinolin-6- yl)oxy)pentyl)piperazin-1-yl)nicotinamide C-1 and Exp. procedure provided as well 47

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,4- tetrahydroisoquinolin-6-yl)oxy)pentyl)piperazin-1- yl)nicotinamide C-1 and Exp. procedureprovided as well 48

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- (5-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro- [1,2,4]triazolo[4,3-a]pyridin-7-yl)oxy)pentyl)piperazin-1- yl)nicotinamide Exp procedure provided 49

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4- (5-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro- [1,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)pentyl)piperazin-1- yl)nicotinamide Exp procedure provided 50

rac-N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- ((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro- [1,2,4]triazolo[4,3-a]pyridin- 7-yl)piperazin-1-yl)methyl)piperidin-1- yl)benzamide Exp procedure provided 51

N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-6- yl)piperazin-1-yl)ethyl)piperidin-1- yl)benzamide C-3, C-4 and Exp procedure provided52

N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- (2-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro- 5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperazin-1- yl)ethyl)piperidin-1- yl)benzamide C-3, c-4 and expprocedure provided

TABLE 3 Exemplary BRaf PROTACs Ex. Synthetic # Chemical Structure NameScheme 39

(E)-2-(2,6-dioxopiperidin-3-yl)-6-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)- 4-phenylisoindoline-1,3-dione D-140

(E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)- 6-methylisoindoline-1,3-dione D-141

(E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)- 4-phenylisoindoline-1,3-dioneCustom synthesis provided 42

(E)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(1-(hydroxyimino)-2,3-dihydro- 1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazin-1-yl)- 4-methylisoindoline-1,3-dioneCustom synthesis provided

TABLE 4 Exemplary BRD4 PROTACs Ex. # Chemical Structure Name 43

2-((R)-4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((1-oxo-2-((R)-6- oxopiperidin-3-yl)isoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy) ethoxy)phenyl)acetamide 44

2-((R)-4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)- 2-methyl-4-oxo-3,4-dihydroquinazolin-8- yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide 45

2-((R)-4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-((3-(2,6-dioxopiperidin-3-yl)- 2-methyl-4-oxo-3,4-dihydroquinazolin-7- yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide

TABLE 5 Characterization of Exemplary Estrogen Receptor PROTACs TargetEx. Observed Engagement ER ER # [M + H]/Z IC₅₀ (nM) DC₅₀* D_(max)* NMR 1743.58 58.2 C B 2 743.58 0.79 B A δ 10.93 (s, 1H), 10.56-10.43 (m, 1H),9.18-9.13 (m, 1H), 7.16-7.13 (m, 3H), 6.84-6.83 (d, J = 6.4 Hz, 2H),6.69 (s, 1H), 6.62-6.61 (m, 2H), 6.55- 6.52 (m, 3H), 6.28-6.26 (d, J =8.4 Hz, 2H), 4.99-4.97 (m, 1H), 4.29-4.25 (m, 1H), 4.23-4.18 (m, 1H),4.17-4.15 (m, 1H), 4.06-4.00 (m, 2H), 3.85- 3.83 (m, 5H), 3.56-3.53 (m,1H), 3.34-3.33 (m, 4H), 3.10-3.02 (m, 4H), 3.00-2.85 (m, 2H), 2.60-2.58(m, 3H), 2.16-2.08 (m, 1H), 1.91-1.88 (m, 1H), 1.76-1.69 (m, 5H),1.43-1.41 (m, 2H). (DMSO-d6, 400 MHz) 3 743.57 1.35 A A δ: 10.96 (s,1H), 9.12 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.25-6.98 (m, 4H), 6.83 (d,J = 6.8 Hz, 2H), 6.72-6.43 (m, 5H), 6.26 (d, J = 8.6 Hz, 2H), 5.06 (dd,J = 5.0, 13.2 Hz, 1H), 4.56-4.11 (m, 3H), 3.94-3.70 (m, 5H), 3.30- 3.25(m, 1H), 3.21-2.77 (m, 8H), 2.64-2.55 (m, 5H), 2.46-2.26 (m, 2H),2.16-1.94 (m, 2H), 1.80-1.22 (m, 7H). (DMSO-d6, 400 MHz) 4 831.65 1.42 AA δ 10.98 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H),7.17- 7.07 (m, 4H), 6.83-6.82 (m, 2H), 6.65-6.60 (m, 2H), 6.54-6.47 (m,3H), 6.27-6.29 (m, 2H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.44-4.40 (m,1H), 4.29-4.17 (m, 4H), 3.81 (t, J = 6.4 Hz, 2H), 3.62-3.60 (m, 3H),3.53- 3.51 (m, 3H), 3.43-3.41 (m, 4H), 3.24-3.17 (m, 6H), 2.97-2.88 (m,4H), 2.78-2.74 (m, 3H), 2.61-2.56 (m, 2H), 2.44-2.37 (m, 2H), 2.10- 1.97(m, 2H), 1.71-1.53 (m, 5H), 1.41-1.38 (m, 2H). (DMSO-d6, 400 MHz) 5842.66 >300 C 6 842.67 2.18 C 7 859.68 102 D B 8 859.68 0.34 B B δ 10.99(s, 1H), 9.12 (s, 1H), 8.16 (s, 1H), 7.36 (s, 2H), 7.17-7.10 (m, 3H),6.83 (d, J = 6.8 Hz, 2H), 6.66-6.59 (m, 2H), 6.52 (d, J = 8.8 Hz, 2H),6.50-6.46 (m, 1H), 6.26 (d, J = 8.4 Hz, 2H), 5.10 (dd, J = 5.2, 13.2 Hz,1H), 4.59 (d, J = 17.2 Hz, 1H), 4.41 (d, J = 17.2 Hz, 1H), 4.22-4.16 (m,3H), 3.82 (t, J = 6.0 Hz, 2H), 3.73-3.67 (m, 2H), 3.60-3.55 (m, 2H),3.48-3.42 (m, 2H), 3.37-3.35 (m, 2H), 3.22 (s, 3H), 3.03-2.82 (m, 6H),2.82-2.69 (m, 10H), 2.63-2.61 (m, 1H), 2.42-2.36 (m, 1H), 2.15-2.04 (m,1H), 2.03- 1.95 (m, 1H), 1.81-1.69 (m, 3H), 1.66-1.60 (m, 2H), 1.58-1.50(m, 2H). (DMSO-d6, 400 MHz) 9 768.61 >300 D B 10 768.61 0.86 B A δ 10.90(s, 1H), 8.28 (s, 1H), 7.19-7.07 (m, 3H), 6.83 (d, J = 6.4 Hz, 2H), 6.64(d, J = 8.4 Hz, 1H), 6.59 (s, 2H), 6.52 (d, J = 8.8 Hz, 2H), 6.49-6.44(m, 2H), 6.19 (d, J = 8.8 Hz, 2H), 5.02-4.91 (m, 1H), 4.96 (dd, J = 5.2,13.2 Hz, 1H), 4.26-4.19 (m, 1H), 4.14-4.06 (m, 2H), 3.82 (s, 3H),3.55-3.45 (m, 2H), 3.30-3.10 (m, 12H), 2.98-2.85 (m, 3H), 2.59-2.53 (m,1H), 2.44-2.41 (m, 1H), 2.38-2.35 (m, 2H), 2.13-2.03 (m, 1H), 1.95-1.87(m, 1H), 1.75-1.65 (m, 3H), 1.48-1.33 (m, 3H), 1.26-1.12 (m, 2H).(DMSO-d6, 400 MHz) 11 798.63 2 B B δ 10.95 (s, 1H), 9.09 (s, 1H), 7.38(d, J = 8.03 Hz, 1H), 7.14 (m, 4H), 6.83 (d, J = 6.53 Hz, 2H), 6.64-6.59(m, 2H), 6.56-6.45 (m, 3H), 6.19 (d, J = 8.66 Hz, 2H), 5.06 (dd, J =12.99, 5.08 Hz, 1H), 4.36-4.27 (m, 1H), 4.19- 4.18 (m, 4H), 3.55-3.53(m, 4H), 3.26 (s, 3H), 3.11 (s, 4H), 2.96 (d, J = 5.9 Hz, 2H), 2.69-2.57(m, 1H), 2.32-2.31 (m, 1H), 2.19 (d, J = 6.65 Hz, 4H), 2.14-2.04 (m,3H), 1.98-1.89 (m, 2H), 11.56 (m, 6H), 1.29-1.01 (m, 3H). (DMSO-d6, 400MHz) 12 779.56 1 A A 10.91 (br s, 1H), 8.20 (s, 1H), 7.19-7.09 (m, 3H),6.84 (br d, J = 6.9 Hz, 2H), 6.67-6.58 (m, 5H), 6.54-6.43 (m, 2H), 6.30(d, J = 8.5 Hz, 2H), 4.97 (dd, J = 5.1, 13.2 Hz, 1H), 4.27-4.07 (m, 5H),3.83 (s, 3H), 3.39-3.28 (m, 5H), 3.04-2.85 (m, 4H), 2.59 (br s, 3H),2.43-2.22 (m, 4H), 2.15-1.88 (m, 4H), 1.82-1.56 (m, 4H). (DMSO-d6, 400MHz) 13 743.58 0.37 A A δ 10.91 (s, 1H), 9.13 (s, 1H), 8.14 (s, 1H),7.18-7.07 (m, 3H), 6.82 (d, J = 6.8 Hz, 2H), 6.69-6.58 (m, 3H),6.55-6.47 (m, 4H), 6.26 (d, J = 8.8 Hz, 2H), 4.96 (dd, J = 5.2, 13.2 Hz,1H), 4.29-4.06 (m, 3H), 3.85-3.78 (m, 5H), 3.30-3.28 (m, 4H), 3.04-2.80(m, 3H), 2.60-2.52 (m, 6H), 2.45- 2.34 (m, 3H), 2.17-1.99 (m, 1H),1.97-1.82 (m, 1H), 1.76-1.58 (m, 3H), 1.56-1.45 (m, 2H), 1.43-1.29 (m,2H). (DMSO-d6, 400 MHz) 14 743.58 0.49 A A δ 10.91 (s, 1H), 9.13 (s,1H), 8.14 (s, 1H), 7.18-7.08 (m, 3H), 6.82 (d, J = 6.8 Hz, 2H),6.66-6.58 (m, 3H), 6.55-6.47 (m, 4H), 6.26 (d, J = 8.8 Hz, 2H), 4.96(dd, J = 5.2, 13.2 Hz, 1H), 4.28-4.10 (m, 3H), 3.85-3.78 (m, 5H),3.30-3.28 (m, 4H), 3.05-2.80 (m, 3H), 2.58-2.51 (m, 6H), 2.38- 2.33 (m,2H), 2.32-2.24 (m, 1H), 2.18-2.00 (m, 1H), 1.97-1.86 (m, 1H), 1.74-1.58(m, 3H), 1.55-1.44 (m, 2H), 1.43-1.34 (m, 2H). (DMSO-d6, 400 MHz) 15754.60 1.7 A A δ 10.91 (s, 1H), 8.23 (s, 2H), 7.17-7.09 (m, 3H), 6.83(d, J = 6.8 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.59 (s, 2H), 6.53 (d, J= 8.8 Hz, 2H), 6.49-6.45 (m, 2H), 6.20 (d, J = 8.8 Hz, 2H), 4.96 (dd, J= 5.0, 13.2 Hz, 1H), 4.25-4.19 (m, 1H), 4.14-4.06 (m, 1H), 4.15-4.06 (m,1H), 3.84-3.80 (m, 3H), 3.51 (d, J = 9.2 Hz, 7H), 3.28 (s, 4H),2.98-2.83 (m, 1H), 3.03-2.82 (m, 2H), 2.58 (s, 1H), 2.32-2.26 (m, 1H),2.22-2.04 (m, 4H), 1.94-1.87 (m, 1H), 1.80-1.55 (m, 5H), 1.21-1.11 (m,2H). (DMSO-d6, 400 MHz) 16 799.6 0.82 A B δ 10.90 (s, 1H), 9.13 (s, 1H),8.14 (s, 1H), 7.01-6.92 (m, 2H), 6.87-6.79 (m, 2H), 6.65 (d, J = 8.4 Hz,1H), 6.60 (s, 2H), 6.55 (d, J = 8.8 Hz, 2H), 6.51- 6.44 (m, 2H), 6.26(d, J = 8.4 Hz, 2H), 4.96 (dd, J = 5.4, 13.4 Hz, 1H), 4.75 (t, J = 4.8Hz, 1H), 4.27-4.06 (m, 3H), 3.85-3.80 (m, 3H), 3.29-3.25 (m, 6H),2.99-2.84 (m, 3H), 2.54 (d, J = 4.4 Hz, 8H), 2.19-1.86 (m, 4H), 1.85-1.58 (m, 5H), 1.24-1.07 (m, 2H). (DMSO-d6, 400 MHz) 17 778.57 1.5 B B δ10.91 (s, 1H), 9.14 (s, 1H), 7.85 (br s, 1H), 7.48-7.34 (m, 2H), 7.18-7.10 (m, 3H), 6.83 (br d, J = 6.7 Hz, 2H), 6.69-6.60 (m, 5H), 6.54-6.47(m, 2H), 6.30 (d, J = 8.5 Hz, 2H), 5.08-4.94 (m, 3H), 4.28-4.17 (m, 2H),4.16-4.08 (m, 1H), 3.84 (s, 4H), 3.66 (br s, 1H), 3.04-2.83 (m, 4H),2.82- 2.71 (m, 1H), 2.68 (br s, 1H), 2.63-2.54 (m, 2H), 2.48-2.26 (m,2H), 2.15-2.03 (m, 1H), 1.97-1.88 (m, 1H), 1.71 (br d, J = 7.5 Hz, 1H).(DMSO-d6, 400 MHz) 18 790.59 17.5 B B 19 790.58 4.5 B A δ 10.89 (s, 1H),8.19 (s, 1H), 7.22-7.16 (m, 3H), 6.90 (br d, J = 6.8 Hz, 2H), 6.68 (d, J= 8.4 Hz, 1H), 6.61 (br d, J = 9.2 Hz, 2H), 6.54-6.50 (m, 1H), 6.47 (s,1H), 5.87 (d, J = 11.2 Hz, 2H), 4.95 (dd, J = 5.2, 13.2 Hz, 1H),4.25-4.20 (m, 2H), 4.13-4.07 (m, 1H), 3.82 (s, 3H), 3.27-3.25 (m, 6H),3.03-2.83 (m, 9H), 2.19 (br d, J = 7.2 Hz, 3H), 2.07-1.89 (m, 3H),1.76-1.58 (m, 5H), 1.16 (br d, J = 9.2 Hz, 2H). (DMSO-d6, 400 MHz) 20779.6 1.2 B B δ 10.96 (s, 1H), 8.20 (s, 1H), 7.62-7.20 (m, 1H),7.18-7.05 (m, 3H), 6.94 (s, 1H), 6.82 (d, J = 6.4 Hz, 2H), 6.71 (s, 1H),6.67-6.58 (m, 2H), 6.56- 6.43 (m, 3H), 6.26 (d, J = 8.8 Hz, 2H), 5.00(dd, J = 5.2, 13.2 Hz, 1H), 4.37- 4.29 (m, 1H), 4.26-4.14 (m, 2H), 3.81(t, J = 6.4 Hz, 2H), 3.31-3.27 (m, 5H), 3.04-2.82 (m, 3H), 2.64-2.52 (m,2H), 2.48-2.42 (m, 3H), 2.41- 2.25 (m, 3H), 2.17-2.02 (m, 1H), 2.00-1.90(m, 1H), 1.75-1.59 (m, 3H), 1.53-1.43 (m, 2H), 1.42-1.32 (m, 2H).(DMSO-d6, 400 MHz) 21 815.6 2.5 B B δ 10.98 (s, 1H), 8.15 (s, 1H),7.68-7.34 (m, 1H), 7.21-7.05 (m, 3H), 6.95 (s, 1H), 6.84 (d, J = 7.2 Hz,2H), 6.73 (s, 1H), 6.68-6.58 (m, 4H), 6.50 (d, J = 8.2 Hz, 1H), 6.31 (d,J = 8.4 Hz, 2H), 5.02 (dd, J = 4.8, 13.2 Hz, 1H), 4.42- 4.27 (m, 1H),4.27-4.04 (m, 4H), 3.31 (s, 4H), 3.03-2.78 (m, 3H), 2.68- 2.55 (m, 1H),2.48 (s, 6H), 2.41-2.32 (m, 3H), 2.16-1.90 (m, 4H), 1.72 (m, 1H), 1.63(m, 2H). (DMSO-d6, 400 MHz) 22 804.6 4.4 B A δ 10.97 (s, 1H), 8.19 (s,1H), 7.68-7.20 (m, 1H), 7.18-7.07 (m, 3H), 6.94 (s, 1H), 6.83 (d, J =6.4 Hz, 2H), 6.71 (s, 1H), 6.66-6.57 (m, 2H), 6.55- 6.43 (m, 3H), 6.19(d, J = 8.4 Hz, 2H), 5.00 (dd, J = 5.0, 13.2 Hz, 1H), 4.38- 4.28 (m,1H), 4.26-4.17 (m, 1H), 4.12 (d, J = 4.6 Hz, 1H), 3.30 (s, 9H),3.01-2.78 (m, 4H), 2.71-2.55 (m, 2H), 2.44-2.26 (m, 5H), 2.16-2.03 (m,1H), 2.02-1.89 (m, 1H), 1.79-1.62 (m, 3H), 1.40 (m, 3H), 1.27- 1.06 (m,2H). (DMSO-d6, 400 MHz) 23 791.6 1.8 B B δ 10.96 (s, 1H), 9.12 (s, 1H),8.16 (s, 1H), 7.63-7.20 (m, 1H), 7.18-7.06 (m, 3H), 6.94 (s, 1H), 6.81(d, J = 6.4 Hz, 2H), 6.71 (s, 1H), 6.67-6.58 (m, 2H), 6.51-6.37 (m, 3H),6.24 (d, J = 8.4 Hz, 2H), 5.00 (dd, J = 5.2, 13.2 Hz, 1H), 4.71-4.60 (m,1H), 4.40-4.29 (m, 1H), 4.26-4.13 (m, 2H), 3.32- 3.27 (m, 9H), 3.04-2.80(m, 3H), 2.63-2.54 (m, 2H), 2.42-2.31 (m, 1H), 2.30-2.19 (m, 3H),2.13-2.03 (m, 4H), 2.02-1.91 (m, 1H), 1.74- 1.51 (m, 3H). (DMSO-d6, 400MHz) 24 786.6 0.7 B A δ 10.89 (s, 1H), 9.17 (s, 1H), 8.32 (s, 1H),7.21-7.10 (m, 3H), 6.86 (d, J = 6.4 Hz, 2H), 6.68-6.58 (m, 4H),6.52-6.44 (m, 2H), 6.08 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 14.2 Hz, 1H),4.95 (dd, J = 5.2, 13.2 Hz, 1H), 4.28-4.16 (m, 2H), 4.14-4.05 (m, 1H),3.83 (s, 3H), 3.18 (s, 2H), 2.99-2.85 (m, 3H), 2.54-2.52 (m, 13H),2.12-1.86 (m, 3H), 1.71 (d, J = 10.8 Hz, 3H), 1.48-1.19 (m, 6H).(DMSO-d6, 400 MHz) 25 715.6 0.5 C 26 769.6 0.7 A A δ 10.90 (s, 1H), 9.16(s, 1H), 7.19-7.09 (m, 3H), 6.82 (br d, J = 6.6 Hz, 2H), 6.68-6.57 (m,3H), 6.53-6.40 (m, 4H), 6.29-6.23 (m, 2H), 4.96 (dd, J = 5.1, 13.3 Hz,1H), 4.53 (quin, J = 7.3 Hz, 1H), 4.31-4.01 (m, 3H), 3.83 (s, 3H), 3.63(br s, 1H), 3.33-3.23 (m, 11H), 3.10 (td, J = 8.8, 17.4 Hz, 1H),3.03-2.79 (m, 3H), 2.55 (br s, 2H), 2.46-2.25 (m, 2H), 2.16- 2.00 (m,3H), 1.99-1.87 (m, 1H), 1.70 (br d, J = 6.0 Hz, 1H). (DMSO-d6, 400 MHz)27 807.6 0.5 A B δ 10.96 (s, 1H), 9.13 (br s, 1H), 8.20-7.39 (m, 1H),7.22-7.08 (m, 3H), 6.97-6.93 (m, 1H), 6.81 (br d, J = 7.7 Hz, 2H),6.73-6.69 (m, 1H), 6.67- 6.62 (m, 1H), 6.60 (d, J = 2.3 Hz, 1H),6.50-6.38 (m, 3H), 6.27-6.21 (m, 2H), 5.00 (br dd, J = 5.1, 13.2 Hz,1H), 4.65 (br t, J = 5.8 Hz, 1H), 4.37- 4.30 (m, 1H), 4.25-4.18 (m, 1H),4.16 (br d, J = 4.9 Hz, 1H), 3.28-3.25 (m, 6H), 3.02-2.81 (m, 3H),2.61-2.53 (m, 4H), 2.45-2.37 (m, 4H), 2.12-1.90 (m, 5H), 1.76-1.64 (m,3H). (DMSO-d6, 400 MHz) 28 771.6 0.3 A A δ 10.91 (s, 1H), 9.13 (s, 1H),8.14 (s, 1H), 7.18-7.08 (m, 3H), 6.81 (br d, J = 7.7 Hz, 2H), 6.66-6.59(m, 3H), 6.51-6.39 (m, 4H), 6.27-6.22 (m, 2H), 4.96 (br dd, J = 5.1,12.9 Hz, 1H), 4.65 (br t, J = 6.3 Hz, 1H), 4.26- 4.19 (m, 1H), 4.16 (brd, J = 4.6 Hz, 1H), 4.13-4.07 (m, 1H), 3.84-3.80 (m, 3H), 3.29-3.23 (m,5H), 3.00-2.84 (m, 3H), 2.62-2.52 (m, 8H), 2.35 (br s, 2H), 2.09-1.88(m, 4H), 1.78-1.66 (m, 3H). (DMSO-d6, 400 MHz) 29 750.6 2.4 C 30 768.62.1 B B δ 10.87 (s, 1H), 9.20 (s, 1H), 8.26 (s, 1H), 7.46 (d, J = 8.8Hz, 1H), 7.24- 7.07 (m, 3H), 6.99 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 6.8Hz, 2H), 6.75-6.56 (m, 4H), 6.50 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 8.0Hz, 1H), 5.97 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 4.4 Hz, 1H), 3.89 (s,1H), 3.35-3.23 (m, 8H), 3.19 (d, J = 6.8 Hz, 3H), 3.05-2.84 (m, 2H),2.76-2.60 (m, 2H), 2.54 (s, 3H), 2.20 (d, J = 6.8 Hz, 2H), 2.06 (dd, J =6.0, 12.0 Hz, 1H), 1.83 (s, 1H), 1.75 (d, J = 12.0 Hz, 3H), 1.62 (s,1H), 1.54-1.44 (m, 2H), 1.44-1.29 (m, 2H), 1.21 (d, J = 10.0 Hz, 2H).(DMSO-d6, 400 MHz) 31 C *ER DC₅₀ (nM) A < 1; 1 <= B < 10; 10 <= C < 100;D >= 100 **ER D_(max) (%) A >= 75; 50 <= B < 75; C < 50

TABLE 6 Characterization of Exemplary Androgen Receptor PROTACs Ex. m/zAR AR # observed DC₅₀* D_(max)** NMR 32 824.54 A 33 852.58 A 34 832.61 C1H NMR (400 MHz, d6-DMSO): δ 10.88 (s, 1H), 8.22 (s, 1H), 7.91 (d, J =8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.53-7.45 (m, 2H), 7.21 (d, J =2.4 Hz, 1H), 6.99 (dd, J = 9.2, 17.6 Hz, 4H), 6.73 (s, 1H), 4.33 (s,1H), 4.06 (d, J = 9.2 Hz, 1H), 3.86 (d, J = 12.4 Hz, 3H), 3.32-3.29 (m,9H), 2.80 (t, J = 12.0 Hz, 3H), 2.59- 2.54 (m, 4H), 2.22 (d, J = 6.8 Hz,2H), 1.81 (d, J = 10.3 Hz, 4H), 1.55-1.47 (m, 2H), 1.45-1.31 (m, 2H),1.25-1.17 (s, 8H), 1.13 (s, 6H) 35 849.6 C 36 849.61 C 37 877.64 C 38877.64 C 46 810.3 A A ¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (6H, s), 1.21(6H, s), 1.43-1.54 (4H, m), 1.74-1.78 (2H, m), 1.88-1.91 (1H, m),2.30-2.44 (8H, m), 2.90-2.97 (3H, m), 3.42-3.59 (7H, m), 4.03-4.07 (3H,m), 4.30 (1H, s), 6.86-6.91 (3H, m), 6.99- 7.02 (1H, m), 7.22 (1H, d, J= 2.4 Hz), 7.64 (1H, d, J = 8.8 Hz), 7.79 (1H, d, J = 8.8 Hz), 7.90-7.97(2H, m), 8.62 (1H, d, J = 2.0 Hz), 10.90 (1H, s). 47 824.3 B B ¹H NMR(400 MHz, DMSO-d⁶) δ 1.12 (6H, s), 1.21 (6H, s), 1.37-1.58 (4H, m),1.73-1.81 (2H, m), 1.86-1.91 (1H, m), 2.30-2.37 (2H, m), 2.40-2.46 (2H,m), 2.82-2.91 (1H, m), 3.30-3.35 (4H, m), 3.55-3.65 (4H, m), 4.03-4.30(6H, m), 5.54-5.63 (1H, m), 6.87 (1H, d, J = 9.6 Hz), 6.96-7.07 (3H, m),7.21 (1H, d, J = 2.4 Hz), 7.63 (1H, d, J = 9.6 Hz), 7.90-8.04 (3H, m),8.62 (1H, d, J = 2.4 Hz), 10.93 (1H, s). 48 798.6 A B ¹H NMR (400 MHz,DMSO-d₆) δ 1.12 (6H, s), 1.21 (6H, s), 1.43-1.47 (2H, m), 1.49-1.53 (2H,m), 1.73-1.78 (2H, m), 2.13-2.17 (1H, m), 2.32 (2H, t, J = 7.2 Hz),2.43-2.47 (5H, m), 2.61-2.62 (1H, m), 2.87-2.93 (1H, m), 3.59 (4H, s),4.01-4.07 (3H, m), 4.30 (1H, s), 5.28 (1H, dd, J = 12.4, 5.2 Hz), 6.35(1H, dd, J = 8.0, 2.4 Hz), 6.52 (1H, d, J = 1.6 Hz), 6.86 (1H, d, J =8.8 Hz), 7.00 (1H, dd, J = 8.8, 2.4 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.63(1H, d, J = 9.2 Hz), 7.80 (1H, d, J = 8.0 Hz), 7.90 (1H, d, J = 8.8 Hz),7.95 (1H, dd, J = 9.2, 2.4 Hz), 8.62 (1H, d, J = 2.4 Hz), 11.09 (1H, s).49 798.6 A A ¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (6H, s), 1.21 (6H, s),1.44-1.48 (2H, m), 1.52-1.58 (2H, m), 1.74-1.79 (2H, m), 2.15-2.19 (1H,m), 2.30 (2H, t, J = 7.2 Hz), 2.43-2.50 (4H, m), 2.51-2.67 (2H, m),2.86-2.95 (1H, m), 3.60 (4H, s), 3.97 (2H, t, J = 6.4 Hz), 4.05 (1H, d,J = 9.2 Hz), 4.30 (1H, s), 5.38 (1H, dd, J = 5.2, 12.8 Hz), 6.86 (1H, d,J = 9.2 Hz), 7.00 (1H, dd, J = 8.4, 2.4 Hz), 7.10 (1H, dd, J = 10.0, 2.0Hz), 7.21 (1H, d, J = 2.4 Hz), 7.25 (1H, d, J = 10.0 Hz), 7.36 (1H, s),7.62 (1H, d, J = 9.2 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.95 (1H, dd, J =9.2, 2.4 Hz), 8.62 (1H, d, J = 2.4 Hz), 11.10 (1H, s). 50 808.6 A A ¹HNMR (400 MHz, DMSO-d⁶) δ 1.13 (6H, s), 1.22 (6H, s), 1.79-1.81 (3H, m),2.09-2.15 (1H, m), 2.19-2.21 (2H, m), 2.49-2.50 (7H, m), 2.60-2.67 (1H,m), 2.76-2.92 (3H, m), 3.22-3.26 (4H, m), 3.86 (2H, d, J = 12.8 Hz),4.05 (1H, d, J = 9.2 Hz), 4.32 (1H, s), 5.23 (1H, dd, J = 12.4, 5.2 Hz),6.12 (1H, s), 6.70 (1H, dd, J = 8.0, 1.6 Hz), 6.95 (2H, d, J = 9.2 Hz),7.00 (1H, dd, J = 8.8, 2.4 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.48 (1H, d, J= 8.8 Hz), 7.72 (3H, t, J = 8.4 Hz), 7.91 (1H, d, J = 8.8 Hz), 11.04(1H, s). 51 835.59 A A 1H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.57(s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.44 (d, J= 9.1 Hz, 1H), 7.29 (s, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.02-6.87 (m,3H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.29 (s, 1H), 4.02 (d, J = 9.1 Hz,1H), 3.88-3.70 (m, 5H), 3.29 (br s, 5H), 2.95-2.65 (m, 3H), 2.59-2.41(m, 6H), 2.00 (m, 1H), 1.73 (d, J = 12.8 Hz, 2H), 1.45 (br, 3H), 1.17(s, 6H), 1.09 (s, 6H) 52 836.59 A B ¹H NMR (400 MHz, d6-DMSO): δ 11.12(s, 1H), 8.90 (s, 1H), 7.91-7.89 (d, J = 8.4 Hz, 1H), 7.74-7.72 (d, J =7.6 Hz, 2H), 7.49-7.47 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 6.99-6.94 (m,3H), 5.16-5.13 (m, 1H), 4.32 (s, 1H), 4.06-3.83 (m, 7H), 2.88-2.57 (m,5H), 2.39-2.33 (m, 2H), 2.07-2.01 (m, 1H), 1.78-1.75 (m, 2H), 1.54-1.35(m, 3H), 1.21 (m, 8H), 1.12 (s, 6H) *AR DC₅₀ (nM) A < 1; 1 <= B < 10; 10<= C < 100; D >= 100 **AR D_(max) (%) A >= 75; 50 <= B < 75; C < 50

TABLE 7 Characterization of Exemplary BRaf PROTACs Ex. BRaf BRaf # DC₅₀*D_(max)** MH+ NMR Transcript 39 C B 783.51 1H NMR (400 MHz, DMSO-d6): δ11.03 (s, 1H), 10.87 (s, 1H), 8.72 (s, 1H), 8.57 (m, 2H), 7.83 (d, J =8.4 Hz, 2H), 7.62-7.60 (m, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.50-7.41 (m,6H), 7.22 (d, J = 8.0 Hz, 2H), 7.17-7.15 (m, 3H), 5.07-5.03 (m, 1H),3.73 (m, 8H), 3.01 (s, 2H), 2.83- 2.81 (m, 3H), 2.67 (s, 2H), 2.03-2.00(m, 1H) 40 C A 721.48 1H NMR (400 MHz, DMSO-d6): δ 11.15 (bs, 1H), 8.72(s, 1H), 8.72 (s, 1H), 8.57 (d, J = 5.6 Hz, 2H), 7.83 (d, J = 8.8 Hz,2H), 7.77 (s, 1H), 7.49-7.57 (m, 4H), 7.41 (s, 1H), 7.17-7.30 (m, 3H),5.09-5.13 (m, 1H), 3.20-3.35 (m, 8H), 2.80-3.12 (m, 6H), 2.52-2.75 (m,3H), 1.90- 2.12 (m, 2H) 41 C A 783.51 1H NMR (400 MHz, DMSO-d6): δ 11.04(s, 1H), 10.88 (s, 1H), 8.69 (s, 1H), 8.57 (d, J = 4.8 Hz, 2H), 7.87 (d,J = 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.40-7.56 (m, 10H), 7.22 (d,J = 4.8 Hz, 1H), 7.03 (d, J = 9.2 Hz, 2H), 5.00-5.05 (m, 1H), 3.02 (m,9H), 2.83 (t, J = 6.8 Hz, 2H), 1.99-2.01 (m, 3H) 42 C B 721.48 1H NMR(400 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.89 (s, 1H), 8.72 (s, 1H),8.58-8.57 (m, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H),7.56 (d, J = 7.6 Hz, 1H), 7.50-7.41 (m, 4H), 7.23-7.17 (m, 3H),5.13-5.09 (m, 1H), 3.61-3.42 (m, 8H), 3.04-2.97 (m, 2H), 2.93-2.82 (m,3H), 2.62-2.56 (m, 5H), 2.08-2.00 (m, 1H) *BRaf DC₅₀ (nM) A < 1; 1 <= B< 10; 10 <= C < 100; D >= 100 **BRaf D_(max) (%) A >= 75; 50 <= B < 75;C < 50

TABLE 8 Characterization of Exemplary BRD4 PROTACs Ex. BRD4 BRD4Observed # DC₅₀* D_(max)** [M + H]+ NMR 43 D B 895.22 ¹H NMR (400 MHz,CHLOROFORM-d) d 9.03 (s, 1H), 7.45 (dd, J = 8.71, 13.21 Hz, 4H),7.31-7.37 (m, 3H), 7.24 (d, J = 7.24 Hz, 1H), 6.84 (d, J = 9.00 Hz, 2H),6.78 (d, J = 8.02 Hz, 1H), 6.75 (br. s., 1H), 4.66-4.73 (m, 2H), 4.20(d, J = 2.74 Hz, 1H), 4.07-4.12 (m, 2H), 3.80-3.90 (m, 3H), 3.64-3.77(m, 10H), 3.52-3.58 (m, 1H), 3.35-3.42 (m, 3H), 2.68 (br. s., 3H),2.52-2.59 (m, 2H), 2.41 (s, 3H), 2.02-2.08 (m, 2H), 1.69 (s, 3H), 1.26(s, 3H). 44 D C 937.19 1H NMR (400 MHz, METHANOL-d4) d 7.60-7.65 (m,1H), 7.30-7.47 (m, 8H), 6.82- 6.87 (m, 2H), 5.24 (dd, J = 5.67, 10.76Hz, 1H), 4.69 (ddd, J = 2.84, 5.62, 8.56 Hz, 1H), 4.26-4.31 (m, 2H),4.02-4.07 (m, 2H), 3.91-3.96 (m, 2H), 3.77-3.81 (m, 2H), 3.70- 3.74 (m,2H), 3.63-3.69 (m, 6H), 3.53-3.61 (m, 1H), 3.43-3.49 (m, 2H), 2.81 (dt,J = 4.60, 14.33 Hz, 2H), 2.70 (s, 6H), 2.43 (s, 3H), 2.13-2.20 (m, 1H),1.68 (s, 2H), 1.26- 1.29 (m, 2H). 45 C A 937.19 ¹H NMR (400 MHz,METHANOL-d4) d 8.55 (s, 1H), 7.96-8.00 (m, 1H), 7.36-7.50 (m, 6H),7.03-7.09 (m, 2H), 6.87 (dd, J = 3.03, 9.10 Hz, 2H), 5.22 (td, J = 5.40,10.91 Hz, 1H), 4.70-4.74 (m, 1H), 4.22 (d, J = 3.33 Hz, 2H), 4.10 (d, J= 4.30 Hz, 2H), 3.85-3.91 (m, 2H), 3.79-3.84 (m, 2H), 3.64-3.71 (m, 7H),3.55-3.64 (m, 2H), 3.42-3.50 (m, 2H), 2.71 (s, 3H), 2.66 (d, J = 3.33Hz, 2H), 2.44 (d, J = 3.33 Hz, 3H), 1.89 (s, 3H), 1.68 (d, J = 3.33 Hz,2H), 1.29 (br. s., 3H). *BRD4 DC₅₀ (nM) A < 1; 1 <= B < 10; 10 <= C <100; D >= 100 **BRD4 D_(max) (%) A >= 75; 50 <= B < 75; C < 50

5. INDUSTRIAL APPLICABILITY

A novel bifunctional molecule, which contains a BRD4 or an androgenreceptor recruiting moiety and an E3 Ligase Cereblon recruiting moiety,through PROTAC technology is described. The bifunctional molecules ofthe present disclosure actively degrades BRD4, leading to significantand persistent downstream MYC suppression and robust cellularproliferation suppression and apoptosis induction. PROTAC mediatedprotein degradation provides a promising strategy in targeting the“undruggable” pathological proteins by traditional approaches.

The contents of all references, patents, pending patent applications andpublished patents, cited throughout this application are herebyexpressly incorporated by reference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims. It is understoodthat the detailed examples and embodiments described herein are given byway of example for illustrative purposes only, and are in no wayconsidered to be limiting to the invention. Various modifications orchanges in light thereof will be suggested to persons skilled in the artand are included within the spirit and purview of this application andare considered within the scope of the appended claims. For example, therelative quantities of the ingredients may be varied to optimize thedesired effects, additional ingredients may be added, and/or similaringredients may be substituted for one or more of the ingredientsdescribed. Additional advantageous features and functionalitiesassociated with the systems, methods, and processes of the presentdisclosure will be apparent from the appended claims. Moreover, thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed is:
 1. A method for detecting whether a molecule cantrigger degradation of a target protein in a cell, the methodcomprising: a) providing a molecule for which the ability to triggerdegradation of a target protein in a cell is to be detected, saidmolecule comprising the structure:CLM-L-PTM wherein CLM is a cereblon E3 ubiquitin ligase binding moietycapable of binding a cereblon E3 ubiquitin ligase in a cell, which CLMis thalidomide, pomalidomide, lenalidomide, or an analog thereof; PTM isa protein targeting moiety, which is a small molecule that binds to anenzyme or receptor, said enzyme or receptor having at least one lysineresidue available to be ubiquitinated by a cereblon E3 ubiquitin ligasebound to the CLM of the molecule, which enzyme or receptor is the targetprotein; and L is a chemical linking group that covalently links the CLMto the PTM to form the molecule; b) incubating a targetprotein-expressing cell in the presence of the molecule of step (a); andc) detecting whether the target protein in the cell has been degraded.2. The method of claim 1, wherein the small molecule of step (a) bindsto a serine/threonine kinase, a tyrosine kinase, a lysinemethyltransferase, RAF, a BCR-Abl tyrosine kinase, HER2/neu, Abl, BRAF,a VEGF receptor, an EGF receptor, a PDGF receptor, c-KIT, FLT3, or ahormone receptor.
 3. The method of claim 1, wherein the small moleculeof step (a) binds to a hormone receptor.
 4. The method of claim 3,wherein the small molecule moiety of step (a) binds to an androgenreceptor.
 5. The method of claim 3, wherein the small molecule moiety ofstep (a) binds to an estrogen receptor.
 6. The method of claim 1,wherein the small molecule of step (a) binds to a serine/threoninekinase.
 7. The method of claim 1, wherein the small molecule of step (a)binds to BRAF.
 8. The method of claim 1, wherein the small molecule ofstep (a) binds to a tyrosine kinase.
 9. The method of claim 1, whereinthe small molecule of step (a) binds to an EGFR or VEGFR.